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Editorial: The Medicinal Chemistry of Novel Approaches for the Treatment of Malaria
[BSP/CTMC/E-Pub/000280]
Marvin J. Meyers
Center for World Health and Medicine
Saint Louis University, Saint Louis
MO 63104
USA
Phone: 1-314-977-5197
Email: mmeyers8@slu.edu
Back to the future: Lessons learned in modern target-based and whole-cell lead optimization of antimalarials
Arnab K. Chatterjee and Bryan K.S. Yeung
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000281]
Recent Advances in Plasmepsin Medicinal Chemistry and Implications for Future Antimalarial Drug Discovery Efforts
Marvin J. Meyers and Daniel E. Goldberg
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000282]
Synthetic Peroxides as Potent Antimalarials. News and Views
Charles W. Jefford
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000283]
Reversed chloroquine molecules as a strategy to overcome resistance in malaria
David H. Peyton
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000284]
Falcipain Inhibition as a Promising Antimalarial Target
Maria Marco and Jose Miguel Coterón
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000285]
Targeting Protein Kinases in the Malaria Parasite: Update of an Antimalarial Drug Target
Veronica M. Zhang, Marina Chavchich and Norman C. Waters
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000286]
Editorial:
Current Advances In Therapeutic Applications of Nuclear Receptors.
Stefano Fiorucci
Dipartimento di Medicina Clinica e Sperimentale,
Università degli Studi di Perugia,
via E. dal Pozzo, 06122 Perugia, Italy.
Tel and Fax +410755855819;
E-mail: barbara.renga@unipg.it
[BSP/CTMC/E-Pub/000287]
General molecular biology and architecture of nuclear receptors
Michal Pawlak, Philippe Lefebvre and Bart Staels
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000288]
Retinoid receptors and therapeutic applications of RAR/RXR modulators
Albane le Maire, Susana Álvarez, Pattabhiraman Shankaranarayanan, Angel R de Lera, William Bourguet and Hinrich Gronemeyer
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000289]
Current status of vitamin D signaling and its therapeutic applications
Carsten Carlberg and Ferdinand Molnár
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000290]
Biology and therapeutic applications of peroxisome proliferator-activated receptors
María P. Menéndez-Gutiérrez, Tamás Rőszer and Mercedes Ricote
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000291]
Update on Cardiovascular safety of PPARgamma agonists and relevance to medicinal chemistry and clinical pharmacology
Andreea Ciudin, Cristina Hernández and Rafael Simó
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000292]
Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders
Stefano Fiorucci, Angela Zampella and Eleonora Distrutti
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000293]
Molecular determinants of Gastrointestinal and liver cancers: Role of Bile acid activated Nuclear Receptors
Barbara Renga, Andrea Mencarelli, Sabrina Cipriani and Eleonora Distrutti
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000294]
Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders
Stefano Fiorucci, Angela Zampella and Eleonora Distrutti
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000295]
Editorial: TB Drug Development
Courtney C. Aldrich
[BSP/CTMC/E-Pub/000296]
Center for Drug Design,
University of Minnesota
516 Delaware St. SE
Minneapolis, MN 55455
Tel: 612-625-7956
Fax: 612-626-8154
Email: aldri015@umn.edu
Targeting InhA, the FASII Enoyl-ACP Reductase: SAR Studies on Novel Inhibitor Scaffolds
Pan Pan and Peter J. Tonge
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000297]
Drug design and identification of potent leads against Mycobacterium tuberculosis thymidine monophosphate kinase
S. Van Calenbergh, S. Pochet and H. Munier-Lehmann
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000298]
Inhibition of 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr): A Review of the Synthesis and Biological Evaluation of Recent Inhibitors
Emily R. Jackson and Cynthia S. Dowd
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000299]
Derivatives of 3-isoxazolecarboxylic acid esters – A potent and selective compound class against replicating and nonreplicating Mycobacterium tuberculosis
Annamaria Lilienkampf, Marco Pieroni, Scott G. Franzblau, William R. Bishai and Alan P. Kozikowski
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000300]
Natural products as leads for tuberculosis drug development
Christine E. Salomon and Lori E. Schmidt
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000301]
Adenylating Enzymes in Mycobacterium tuberculosis as Drug Targets
Benjamin P. Duckworth, Kathryn M. Nelson and Courtney C. Aldrich
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000302]
Editorial: QSAR/QSPR Models as Enabling Technologies for Drug & Targets Discovery in: Medicinal Chemistry, Microbiology-Parasitology, Neurosciences, Bioinformatics, Proteomics and other Biomedical Sciences
Humberto González-Díaz, Ph.D.
Faculty of Pharmacy
University of Santiago de Compostela
Santiago de Compostela, 15782
Spain.
gonzalezdiazh@yahoo.es
[BSP/CTMC/E-Pub/000303]
Computer-aided drug design methodologies toward the design of anti-hepatitis C agents
Alejandro Speck-Planche and M. Natália D. S. Cordeiro
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000304]
Structure-based Analysis of the Molecular Recognitions between HIV-1 TAR-RNA and Transcription Factor Nuclear Factor-kappaB (NFkB)
Mahmud Tareq Hassan Khan, Carlo Mischiati, Arjumand Ather, Tatsuya Ohyama, Kenichi Dedachi, Monica Borgatti, Noriyuki Kurita and Roberto Gambari
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000305]
Review of Synthesis, Assay, and Prediction of β and γ-secretase inhibitors
Helena Niño, José Enrique Rodríguez-Borges, Xerardo García-Mera and
Francisco Prado-Prado
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000306]
Conotoxins: Review and Docking Studies to determine potentials of Conotoxin as an Anticancer Drug Molecule
Anasuya Lahiry and Kirtan Dave
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000307]
A Review of QSAR studies to Discover New Drug-like Compounds Actives against Leishmaniasis and Trypanosomiasis
Juan Alberto Castillo-Garit, Concepción Abad, J. Enrique Rodríguez-Borges, Yovani Marrero-Ponce and Francisco Torrens
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000308]
Freely accessible databases of commercial compounds for high-throughput virtual screenings
Arménio Jorge Moura Barbosa and Alberto Del Rio
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000309]
Recent advances on A3 adenosine receptor antagonists by QSAR tools
Feng Luan, Fernanda Borges and M. Natália D. S. Cordeiro
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000310]
Review of Synthesis, Biological assay, and QSAR studies of HMGR inhibitors
Isela García, Yagamare Fall Diop and Generosa Gómez
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000311]
Genomic Sequence Analysis of EGFR Regulation by MicroRNAs in Lung Cancer
Lawrence WC Chan and Feng F Wang
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000312]
From QSAR models of Drugs to Complex Networks: State-of-Art Review and Introduction of New Markov-Spectral Moments Indices
Pablo Riera-Fernández, Raquel Martín-Romalde, Francisco J Prado-Prado, Manuel Escobar Cristian R. Munteanu, Riccardo Concu, Aliuska Duardo-Sanchez and Humberto González-Díaz
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000313]
Editorial: Recent Developments in the Drug Discovery of Epilepsy
Waquar Ahsan, Ph.D. Dept. of Pharm. Chemistry, College of Pharmacy, Jazan University Jazan, Saudi Arabia, E-mail address:
waquarahsan@gmail.com
[BSP/CTMC/E-Pub/000314]
Glutamatergic neurotransmission as molecular target of new anticonvulsants
Rosaria Gitto, Laura De Luca, Sara De Grazia and Alba Chimirri
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000315]
Recent Progress in Anticonvulsant Drug Research: Strategies for Anticonvulsant Drug Development and Applications of Antiepileptic Drugs for Non-Epileptic Central Nervous System Disorders
Sevim Dalkara and Arzu Karakurt
[Abstract] [Purchase Article] [BSP/CTMC/E-Pub/000316]
Targeting Oxidative Stress Component in the Therapeutics of Epilepsy
Faizul Azam, M.V.V. Prasad and Neelaveni Thangavel
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000317]
An Insight into the New Anticonvulsant Agents
Waquar Ahsan, Mohsin M. Safhi, Nadeem Siddiqui, Shamama Javed, M Shamsher Alam, Bishmillah Azad and Jawaid Akhtar
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000318]
Sodium Channel Blockers as Therapeutic Target for Treating Epilepsy: Recent Updates
Valentina Zuliani, Marco Fantini and Mirko Rivara
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000319]
Genome-wide expression analysis in epilepsy: a synthetic review
Abhay Sharma
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000320]
Editorial: Pharmaceutical R&D: A Knowledge-Intensive MultiDisciplinary Approach
[BSP/CTMC/E-Pub/000321]
Gary W. Caldwell
Recent Advances in Positron Emission Tomography (PET) Radiotracers for Imaging Phosphodiesterases
José Ignacio Andrés, Meri De Angelis, Jesús Alcázar, Sofie Celen and Guy Bormans
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000322]
A Novel Method for Determination of Drug Distribution in Rat Brain Tissue Sections by LC/MS/MS: Functional Tissue Microanalysis
John A. Masucci, Andrew D. Mahan, Joseph D. Kwasnoski and Gary W. Caldwell
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000323]
Screening Strategy for Chiral and Achiral Separations in Supercritical Fluid Chromatography Mode
David Speybrouck, David Corens and Jean-Michel Argoullon
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000324]
Chromatographic Separation of Bioactive Oxycholesterols by GC, HPLC and SFC
Heather McAllister and Jiejun Wu
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000325]
Insights from Structural Analysis of cFMS/Inhibitor Complexes: Common Interactions via Three Structurally Dissimilar Scaffolds
Renee L. DesJarlais
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000326]
The IC50 Concept Revisited
Gary W. Caldwell, Zhengyin Yan, Wensheng LangandJohn A. Masucci
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000327]
The Current Status of Time Dependent CYP Inhibition Assay and In Silico Drug-drug Interaction Predictions
Zhengyin Yan and Gary W. Caldwell
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000328]
Small Molecule Compound Logistics Outsourcing – Going beyond the “Thought Experiment”
Devon L. Ramsay, Joseph D. Kwasnoski and Gary W. Caldwell
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000329]
An Integrated Data Management Framework for Drug Discovery – From Data Capturing to Decision Support
Walter Cedeño, Simson Alex, Edward P. Jaeger, Dimitris Agrafiotis and Victor Lobanov
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/00030]
Abstracts
Back to the future: Lessons learned in modern target-based and whole-cell lead optimization of antimalarials
Arnab K. Chatterjee and Bryan K.S. Yeung
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000281]
Antimalarial drug discovery has historically benefitted from the whole-cell (phenotypic) screening approach to identify lead molecules in the search for new drugs. However over the past two decades there has been a shift in the pharmaceutical industry to move away from whole-cell screening to target-based approaches. As part of a Wellcome Trust and Medicines for Malaria Venture (MMV) funded consortium to discover new blood-stage antimalarials, we used both approaches to identify new antimalarial chemotypes, two of which have progressed beyond the lead optimization phase and display excellent in vivo efficacy in mice. These two advanced series were identified through a cell-based optimization devoid of target information and in this review we summarize the advantages of this approach versus a target-based optimization. Although the each lead optimization required slightly different medicinal chemistry strategies, we observed some common issues across the different the scaffolds which could be applied to other cell based lead optimization programs.
[Back to top]
Recent Advances in Plasmepsin Medicinal Chemistry and Implications for Future Antimalarial Drug Discovery Efforts
Marvin J. Meyers and Daniel E. Goldberg
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000282]
Plasmepsins are the aspartic proteases of Plasmodium that play key roles in the survival of the parasite in its host. The plasmepsins of the digestive vacuole play an important role in hemoglobin degradation, providing the parasite with a vital source of nutrients. Recently, plasmepsin V has been shown to be an essential protease, processing hundreds of parasite proteins for export into the host erythrocyte. The functions of the remaining plasmepsins have yet to be discovered. Over the past decade, much effort has been placed towards developing plasmepsin inhibitors as antimalarial agents, particularly targeting the digestive vacuole. This review will highlight some of the recent work in this field with a particular focus on target druggability and strategies for identifying plasmepsins inhibitors as effective antimalarial drugs. Given recent advances in understanding the fundamental roles of the various plasmepsins, it is likely that the most effective antimalarial plasmepsin targets will be the non-digestive vacuole plasmepsins.
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Synthetic Peroxides as Potent Antimalarials. News and Views
Charles W. Jefford
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000283]
The present review describes the development of synthetic cyclic peroxides, which are designed to surpass the antimalarial activity of the lead molecule, the natural product (+)-artemisinin and some of its C10 derivatives. To begin with, tricyclic and bicyclic 1,2,4-trioxanes are taken to show how the pharmacophore was identified and chirality proved to be irrelevant. The action of ferrous salts on trioxanes illustrates the structural elements that are needed so that reductive breaking of the peroxide bond leads to C-centered radicals, the alleged parasiticidal agents. Views are expressed on how heme, Plasmodium SERCA, and plain ferrous ions, either as targets or activators, could be implicated in the mode of action. Thereafter, news about 1,2,4-trioxolanes, 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, 1,2-dioxolanes, and 1,2-dioxanes is recounted, emphasizing aspects of design, mechanism, and the importance of the adamantane entity for buttressing activity. News about compounds made up of a trioxane covalently bound to aminoquinoline, so-called hybrid molecules, is reported together with a view that they might be better than mechanical mixtures. No new antimalarial can be considered without a word about the risk posed by the parasite developing resistance. The review is not intended to be exhaustive. Some gaps prior to 2009 are filled in, while the later literature up to the end of July 2011 has been covered. Artemisinin and its derivatives fall outside the scope of the review. Nevertheless, some mechanistic insights garnered from artemisinin, which are relevant to synthetic peroxides, are included.
[Back to top]
Reversed chloroquine molecules as a strategy to overcome resistance in malaria
David H. Peyton
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000284]
This short review tells the story of how Reversed Chloroquine drugs (RCQs) were developed. These are hybrid molecules, made by combining the quinoline nucleus from chloroquine (CQ) with moieties which are designed to inhibit efflux via known transporters in the membrane of the digestive vacuole of the malaria parasite. The resulting RCQ drugs can have potencies exceeding that of CQ, while at the same time having physical chemical characteristics that may make them favorable as partner drugs in combination therapies. The need for such novel antimalarial drugs will continue for the foreseen time.
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Falcipain Inhibition as a Promising Antimalarial Target
Maria Marco and Jose Miguel Coterón
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000285]
Falcipains are Plasmodium falciparum cysteine proteases involved in different processes of the erythrocytic cycle of the malaria parasite like hydrolysis of host hemoglobin, erythrocyte invasion, and erythrocyte rupture. These proteases constitute promising targets in the search for novel therapies that would ease the burden caused by the increasing resistance to current antimalarial drugs. Despite biochemical characterization of four falcipains so far, the search for new falcipain inhibitors has been limited to falcipain-2 and/ or falcipain-3, due to their interesting hemoglobinase capacity and the ample availability of tools to study them. We describe progress towards the discovery of promising falcipain inhibitors, in the light of their drug-like properties and the effect of the inhibition of several of these cysteine proteases. Some important aspects to focus on future development of falcipain inhibition are also discussed.
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Targeting Protein Kinases in the Malaria Parasite: Update of an Antimalarial Drug Target
Veronica M. Zhang, Marina Chavchich and Norman C. Waters
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000286]
Millions of deaths each year are attributed to malaria worldwide. Transmitted through the bite of an Anopheles mosquito, infection and subsequent death from the Plasmodium species, most notably P. falciparum, can readily spread through a susceptible population. A malaria vaccine does not exist and resistance to virtually every antimalarial drug predicts that mortality and morbidity associated with this disease will increase. With only a few antimalarial drugs currently in the pipeline, new therapeutic options and novel chemotypes are desperately needed. Hit-to-Lead diversity may successfully provide novel inhibitory scaffolds when essential enzymes are targeted, for example, the plasmodial protein kinases. Throughout the entire life cycle of the malaria parasite, protein kinases are essential for growth and development. Ongoing efforts continue to characterize these kinases, while simultaneously pursuing them as antimalarial drug targets. A collection of structural data, inhibitory profiles and target validation has set the foundation and support for targeting the malarial kinome. Pursuing protein kinases as cancer drug targets has generated a wealth of information on the inhibitory strategies that can be useful for antimalarial drug discovery. In this review, progress on selected protein kinases is described. As the search for novel antimalarials continues, an understanding of the phosphor-regulatory pathways will not only validate protein kinase targets, but also will identify novel chemotypes to thwart malaria drug resistance.
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General molecular biology and architecture of nuclear receptors
Michal Pawlak, Philippe Lefebvre and Bart Staels
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000288]
Nuclear receptors (NRs) regulate and coordinate multiple processes by integrating internal and external signals, thereby maintaining homeostasis in front of nutritional, behavioral and environment challenges. NRs exhibit strong similarities in their structure and mode of action: by selective transcriptional activation or repression of cognate target genes, which can either be controlled through a direct, DNA binding-dependent mechanism or through crosstalk with other transcriptional regulators, NRs modulate the expression of gene clusters thus achieving coordinated tissue responses. Additionally, non genomic effects of NR ligands appear mediated by ill-defined mechanisms at the plasma membrane. These effects mediate potential therapeutic effects as small lipophilic molecule targets, and many efforts have been put in elucidating their precise mechanism of action and pathophysiological roles. Currently, numerous nuclear receptor ligand analogs are used in therapy or are tested in clinical trials against various diseases such as hypertriglyceridemia, atherosclerosis, diabetes, allergies and cancer and others.
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Retinoid receptors and therapeutic applications of RAR/RXR modulators
Albane le Maire, Susana Álvarez, Pattabhiraman Shankaranarayanan, Angel R de Lera, William Bourguet and Hinrich Gronemeyer
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000289]
Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth, differentiation, survival and death. Due to their regulatory potential, these nuclear receptors (NRs) are major drug targets for a variety of pathologies, including cancer and metabolic diseases. A large amount of RAR- and RXR-selective ligands, ranging from (partial) agonists to antagonists and inverse agonists, have been designed and the corresponding structural and functional analyses have provided deep insight into the molecular basis of ligand action. Ligands regulate, via allosteric conformational changes, the ability of these NRs to interact with different sets of coregulators, which in turn recruit enzymatically active complexes/machineries. Here, we describe strategies in the design of selective RXR and RAR modulators and review the structural mechanisms by which the diverse pharmacological classes of compounds modulate receptor functions. Finally, we discuss the perspectives for retinoid- and rexinoid-based therapies.
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Current status of vitamin D signaling and its therapeutic applications
Carsten Carlberg and Ferdinand Molnár
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000290]
Vitamin D and in particular its biologically most active metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are central endocrine molecules that influence many aspects of human physiology, which are not only the well-known calcium and phosphorus up-take and transport controlling bone formation, but also the control of immune functions and of cellular growth and differentiation. Basically all actions of 1α,25(OH)2D3 are mediated by the transcription factor vitamin D receptor (VDR). The crystal structure of the VDR and detailed knowledge on its molecular interactions with the ligand provide significant insight into the mechanisms of vitamin D signaling. This applies also on the action of the huge number of synthetic 1α,25(OH)2D3 analogues, which have been developed with the goal of a therapeutic application in hyper-proliferative diseases, such as psoriasis, benign prostate hyperplasia and different types of cancer, in immune functions, such as autoimmune diseases and microbial infections, or in bone disorders, such as osteoporosis. Moreover, detailed investigations on many VDR target genes and in particular the recently available genome-wide view on vitamin D signaling allows a more complete view on the potential of the nuclear hormone. In this review we discuss the latest insight into vitamin D signaling in context with the most prominent 1α,25(OH)2D3 analogues.
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Biology and therapeutic applications of peroxisome proliferator-activated receptors
María P. Menéndez-Gutiérrez, Tamás Rőszer and Mercedes Ricote
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000291]
Peroxisome proliferator-activated receptors (PPARs) are ligand dependent transcription factors. The three mammalian PPARs are key regulators of fatty acid and lipoprotein metabolism, glucose homeostasis, cellular proliferation/differentiation and the immune response. PPARs are therefore important targets in the treatment of metabolic disorders such as insulin resistance and type 2 diabetes mellitus, and are also of interest in relation to chronic inflammatory diseases such as atherosclerosis, arthritis, chronic pulmonary inflammation, pancreatitis, inflammatory bowel disease, and psoriasis. Recent advances have attributed novel functions to PPARs in blood pressure regulation, neuroinflammation, nerve-cell protection, inflammatory pain reduction, and the hypothalamic control of metabolism. The abundant pleiotropic actions of PPARs suggest that PPAR agonists have enormous therapeutic potential. However, current PPAR-based therapies often have undesired side effects due to the concomitant activation of PPARs in non-target cells. There is therefore growing interest in the development of cell-specific PPAR agonists and improvement of the clinical use of PPAR ligands. This review gives an overview of PPAR functions and discusses the current and potential medical implications of PPAR ligands in various pathologies, ranging from metabolic disorders to cardiovascular disease, chronic inflammation, neurodegenerative disorders and cancer.
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Update on Cardiovascular safety of PPARgamma agonists and relevance to medicinal chemistry and clinical pharmacology
Andreea Ciudin, Cristina Hernández and Rafael Simó
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000292]
Peroxisome proliferator-activator receptors (PPARs) are now known as members of the nuclear hormone-receptor superfamily of ligand-activated transcription factors that regulate gene expression in response to nutritional and physiological stimuli. PPARγ plays a crucial role in glucose homeostasis and it is involved in the regulation of lipid metabolism and adipocyte differentiation and function. From all the PAARγ ligands, the thiazolidindiones (TZDs) are of most clinical importance. Rosiglitazone and pioglitazone have been largely used so far in the clinical practice provide similar effects on glycemic control, as well as a range of similar adverse effects, such as weight gain, fluid retention, and increased risk of heart failure, which seem to be PPARγ mediated. Interestingly, they differ on their effect on lipid and cardiovascular safety profile, indicating a PPARγ-independent mechanism. Indeed, rosiglitazone was recently withdrawn in Europe and its use has been restricted in USA as a consequence of increased risk of cardiovascular events in type 3 diabetic patients. This review is focused on the cardiovascular effects of rosiglitazone and pioglitazone as representative members of PPARγ ligands, because they were widely evaluated in many clinical trials and experimental studies and data obtained from these studies are relevant from medicinal chemistry and clinical pharmacology point of view. Finally, an overview on the development of selective PPARγ modulators and/or dual PPARα/γ agonists will be given. These new approaches might provide anti-hyperglycemic efficacy without the associated undesirable side-effects. However, further experimental and clinical studies evaluating the theoretical benefit and safety of this therapeutic strategy are needed.
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Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders
Stefano Fiorucci, Angela Zampella and Eleonora Distrutti
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000293]
The farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR) are ligand regulated nuclear receptors highly expressed in the liver and intestine supervising essential steps in the metabolism of xeno and endo-biotics in entero-hepatic tissues. Primary and secondary bile acids function as receptor agonists/activators for these receptors. Activation of FXR by steroidal and non steroidal ligands promotes bile acids secretion by activating bile acids transporters in the apical membrane of hepatocytes. These effects are coordinated with a reduction in bile acids uptake at the basolateral membrane. However, FXR agonists interfere with the regulatory activity of CAR on hepatocyte’s basolateral transporters. Because these effects might worsen live injury in a subset of patients with obstructive cholestasis, development of FXR antagonists might be of clinical relevance. Structure-activity relationship studies have shown that available FXR antagonists are poorly specific for FXR, however the recent discovery of selective antagonists from marine organisms has ground the identification/development of specific FXR antagonists that are currently used in pre-clinical models of liver injury. PXR agonists are endowed with a wide array of biological activities but their effects on the expression/activity of phase I and II metabolizing enzymes is likely to limit their pharmacological development. Nevertheless a combination between FXR agonists and CAR and PXR agonists might hold utility in treating subset of patients with liver disorders. In addition, development of FXR modulators, or tissue specific agonists, is an attractive opportunity to target subsets of genes in the intestine and liver avoid side-effects linked to FXR activation.
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Molecular determinants of Gastrointestinal and liver cancers: Role of Bile acid activated Nuclear Receptors
Barbara Renga, Andrea Mencarelli, Sabrina Cipriani and Eleonora Distrutti
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000294]
Invasion and metastasis are critical determinants un gastrointestinal and liver cancers morbidity. Genes and molecules participating in these steps (e.g. growth factors and their receptors, cell cycle regulators, cell adhesion molecules, matrix degrading enzyme) have been progressively clarified. Activated Wnt signaling pathway has been found in these tumors. Mutations in one of the DNA mismatch repair genes, alterations in epigenetics, such as aberrant DNA methylation and histone modifications are associated with the progression of gastrointestinal and liver neoplasies. Bile acids (BAs), the main constituents of bile, activate a family of nuclear receptors (NRs) that controls critical steps in bile acid homeostasis, endo- and xenobiotics detoxification, glucose, lipid metabolism and innate immunity. BAs activated NRs are misregulated in gastrointestinal and liver cancers. The present review provide an overview on the molecular determinants involved in gastrointestinal and liver cancers and focuses on the role of BAs activated NRs in the pathogenesis of these tumors.
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Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders
Stefano Fiorucci, Angela Zampella and Eleonora Distrutti
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000295]
The farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR) are ligand regulated nuclear receptors highly expressed in the liver and intestine supervising essential steps in the metabolism of xeno and endo-biotics in entero-hepatic tissues. Primary and secondary bile acids function as receptor agonists/activators for these receptors. Activation of FXR by steroidal and non steroidal ligands promotes bile acids secretion by activating bile acids transporters in the apical membrane of hepatocytes. These effects are coordinated with a reduction in bile acids uptake at the basolateral membrane. However, FXR agonists interfere with the regulatory activity of CAR on hepatocyte’s basolateral transporters. Because these effects might worsen live injury in a subset of patients with obstructive cholestasis, development of FXR antagonists might be of clinical relevance. Structure-activity relationship studies have shown that available FXR antagonists are poorly specific for FXR, however the recent discovery of selective antagonists from marine sponges has ground the identification/development of specific FXR antagonists that are currently used in pre-clinical models of liver injury. PXR agonists are endowed with a wide array of biological activities but their effects on the expression/activity of phase I and II metabolizing enzymes is likely to limit their pharmacological development. Nevertheless a combination between FXR agonists and CAR and PXR agonists might hold utility in treating subset of patients with liver disorders. In addition, development of tissue specific FXR antagonists is an attractive opportunity to target subsets of genes in the intestine and liver avoid side-effects linked to FXR activation.
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Targeting InhA, the FASII Enoyl-ACP Reductase: SAR Studies on Novel Inhibitor Scaffolds
Pan Pan and Peter J. Tonge
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000297]
The bacterial type II fatty acid biosynthesis (FASII) pathway is an essential but unexploited target for drug discovery. In this review we summarize SAR studies on inhibitors of InhA, the enoyl-ACP reductase from the FASII pathway in M. tuberculosis. Inhibitor scaffolds that are described include the diaryl ethers, pyrrolidine carboxamides, piperazine indoleformamides, pyrazoles, arylamides, fatty acids, and imidazopiperidines, all of which form ternary complexes with InhA and the NAD cofactor, as well as isoniazid and the diazaborines which covalently modify the cofactor. Analysis of the structural data has enabled the development of a common binding mode for the ternary complex inhibitors, which includes a hydrogen bond network, a large hydrophobic pocket and a third ‘size-limited’ binding area comprised of both polar and non-polar groups. A critical factor in InhA inhibition involves ordering of the substrate binding loop, located close to the active site, and a direct link is proposed between loop ordering and slow onset enzyme inhibition. Slow onset inhibitors have long residence times on the enzyme target, a property that is of critical importance for in vivo activity.
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Drug design and identification of potent leads against Mycobacterium tuberculosis thymidine monophosphate kinase
S. Van Calenbergh, S. Pochet and H. Munier-Lehmann
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000298]
Antiviral chemotherapy often relies on nucleoside analogues, which, once phophorylated by intracellular kinases, target viral polymerases impeding DNA synthesis. In contrast, nucleoside analogues are much less explored as antibacterial drugs. Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), which is essential to DNA replication, was selected as a promising target for the design of new inhibitors. This review describes stepwise modifications of the TMPKmt substrate, guided by the feedback of enzyme assays and crystallographic analysis to afford potent enzyme inhibitors some of which also exhibited antitubercular activity. More importantly, several of the reported thymidine analogues provided a deeper understanding of the structure and catalytic mechanism of this intriguing enzyme.
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Inhibition of 1-Deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr): A Review of the Synthesis and Biological Evaluation of Recent Inhibitors
Emily R. Jackson and Cynthia S. Dowd
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000299]
Isoprene biosynthesis is an essential component of metabolism. Two pathways are known for the production of five-carbon (isoprene) intermediates: the mevalonate and nonmevalonate pathways. As many pathogenic organisms rely exclusively on the nonmevalonate pathway (NMP) for isoprenoids and humans do not, the enzymes of this route have been recently explored as new therapeutic targets. The second and first-committed step in the NMP is 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr) and has received significant attention as a novel drug target. This review describes the biochemistry and crystal structures of Dxr and the synthesis and biological activity of inhibitors to date, with a focus on compounds targeting E. coli, Plasmodium, and M. tuberculosis enzymes and intact cells. Most inhibitors for Dxr use natural products fosmidomycin and FR900098 as starting points. The review discusses several families of fosmidomycin-related analogs including α-substituted, ‘reverse’ and modified hydroxamate, spacer-modified, and hydroxy-amide analogs. Also discussed are non-fosmidomycin-like inhibitors, the aryl phosphonates, and lipophilic prodrugs of fosmidomycin and FR900098 designed to increase cell penetration. A comprehensive SAR of inhibitors of presented.
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Derivatives of 3-isoxazolecarboxylic acid esters – A potent and selective compound class against replicating and nonreplicating Mycobacterium tuberculosis
Annamaria Lilienkampf, Marco Pieroni, Scott G. Franzblau, William R. Bishai and Alan P. Kozikowski
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000300]
New antituberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis (Mtb) strains and to shorten the long treatment regimen. A series of isoxazole-based compounds, bearing a carboxy moiety at the C3 position, are highly potent and versatile anti-TB agents. Several members of this compound class exhibit submicromolar in vitro activity against replicating Mtb (R-TB) and thus comparable activity to the current first-line anti-TB drugs. Remarkably, certain compounds also show low micromolar activity in a model for nonreplicating Mtb (NRP-TB) phenotype, which is considered a key to shortening the current long treatment protocol. The series shows excellent selectivity towards Mtb and, in general, shows no cytotoxicity on Vero cells (IC50’s > 128 μM). Selected compounds retain their activity against isoniazid (INH), rifampin (RMP), and streptomycin (SM) resistant Mtb strains. The foregoing facts make derivatives of 3-isoxazolecarboxylic acid esters a promising anti-TB chemotype, and as such present attractive lead compounds for TB drug development.
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Natural products as leads for tuberculosis drug development
Christine E. Salomon and Lori E. Schmidt
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000301]
New therapeutics are urgently needed to combat the immense disease burden of tuberculosis and related mycobacterial diseases worldwide. Natural products continue to provide leads for the development of novel drugs to treat the rapidly growing numbers of patients with multi- and extensively-drug resistant tuberculosis. This review presents natural products and synthesized analogues with anti-mycobacterial activity published between 2006 through 2009. Structure activity relationships, synthetic analogues and newly reported activities of known compounds reported during this period are also included.
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Adenylating Enzymes in Mycobacterium tuberculosis as Drug Targets
Benjamin P. Duckworth, Kathryn M. Nelson and Courtney C. Aldrich
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000302]
Adenylation or adenylate-forming enzymes (AEs) are widely found in nature and are responsible for the activation of carboxylic acids to intermediate acyladenylates, which are mixed anhydrides of AMP. In a second reaction, AEs catalyze the transfer of the acyl group of the acyladenylate onto a nucleophilic amino, alcohol, or thiol group of an acceptor molecule leading to amide, ester, and thioester products, respectively. Mycobacterium tuberculosis encodes for more than 60 adenylating enzymes, many of which represent potential drug targets due to their confirmed essentiality or requirement for virulence. Several strategies have been used to develop potent and selective AE inhibitors including high-throughput screening, fragment-based screening, and the rationale design of bisubstrate inhibitors that mimic the acyladenylate. In this review, a comprehensive analysis of the mycobacterial adenylating enzymes will be presented with a focus on the identification of small molecule inhibitors. Specifically, this review will cover the aminoacyl tRNA-synthetases (aaRSs), MenE required for menaquinone synthesis, the FadD family of enzymes including the fatty acyl-AMP ligases (FAAL) and the fatty acyl-CoA ligases (FACLs) involved in lipid metabolism, and the nonribosomal peptide synthetase adenylation enzyme MbtA that is necessary for mycobactin synthesis. Additionally, the enzymes NadE, GuaA, PanC, and MshC involved in the respective synthesis of NAD, guanine, pantothenate, and mycothiol will be discussed as well as BirA that is responsible for biotinylation of the acyl CoA-carboxylases.
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Computer-aided drug design methodologies toward the design of anti-hepatitis C agents
Alejandro Speck-Planche and M. Natália D. S. Cordeiro
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000304]
Hepatitis C constitutes an infectious disease that causes severe damages to the liver, and is caused by hepatitis C virus. There is no vaccine against this type of disease and the number of people infected continues to grow worldwide. The anti-viral therapy which is currently used is a mixture of interferon alpha-2a with ribavirin, but approximately half of the patients do not respond to therapy. Therefore, it is necessary to search for new compounds with anti-hepatitis C activity. Computer-aided drug design methodologies have been vital in the discovery of candidates to drugs. This review is dedicated to the role of computer-aided drug design methodologies for the development of new anti-hepatitis C agents. In addition, we introduce a QSAR model based on substructural approaches in order to model the anti-hepatitis C activity in vivo.
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Structure-based Analysis of the Molecular Recognitions between HIV-1 TAR-RNA and Transcription Factor Nuclear Factor-kappaB (NFkB)
Mahmud Tareq Hassan Khan, Carlo Mischiati, Arjumand Ather, Tatsuya Ohyama, Kenichi Dedachi, Monica Borgatti, Noriyuki Kurita and Roberto Gambari
[Abstract] [FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000305]
In this paper we applied the “macromolecular docking” procedure to perform molecular modeling with the aim of screening transcription factor sequences for possible interaction to the HIV-1 TAR-RNA, employing the software Hex version 4.2. The molecular modeling data were compared with electrophoretic mobility shift assays (EMSA) and surface plasmon resonance (SPR) based biospecific interaction analysis (BIA) using an optical biosensor. Finally the specific interactions between NF-κB and RNA have been calculated utilizing the AMBER-MM and FMO calculations. The results obtained clearly indicate that (a) NF-kB p50 transcription factor can bind TAR-RNA; (b) this binding efficiency is lower than that displayed by NF-kB factor in respect to DNA sequences; (c) other structured RNAs used as controls do not bind to NF-kB; (d) TAR-RNA is capable to bind pre-formed NF-kB/DNA complexes. Despite the fact that our data do not indicate whether NF-kB/TAR-RNA complexes play a role in the early steps of HIV-1 transcriptional activation, the results presented strongly indicate that interactions between transcription factors recruited at the level of HIV-1 LTR might interact with the TAR-RNA and deserve further studies aimed to determine its role in the HIV-1 life cycle.
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Review of Synthesis, Assay, and Prediction of β and γ-secretase inhibitors
Helena Niño, José Enrique Rodríguez-Borges, Xerardo García-Mera and
Francisco Prado-Prado
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000306]
Alzheimer's disease (AD) is characterize with several pathologies this disease, amyloid plaques, composed of the β-amyloid peptide and γ-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. AD is the most prevalent form of dementia, and current indications show that twenty-nine million people live with AD worldwide, a figure expected rise exponentially over the coming decades. Clearly, blocking disease progression or, in the best-case scenario, preventing AD altogether would be of benefit in both social and economic terms. However, current AD therapies are merely palliative and only temporarily slow cognitive decline, and treatments that address the underlying pathologic mechanisms of AD are completely lacking. While familial AD (FAD) is caused by autosomal dominant mutations in either amyloid precursor protein (APP) or the presenilin (PS1, PS2) genes. First, we revised Desing, synthesis, and Biological assay of β and γ-secretase inhibitors. Next, we review 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compound to find out the structural requirements. Next, we revised QSAR studies using method of Artificial Neural Network (ANN) in order to understand the essential structural requirement for binding with receptor for β and γ-secretase inhibitors.
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Conotoxins: Review and Docking Studies to determine potentials of Conotoxin as an Anticancer Drug Molecule
Anasuya Lahiry and Kirtan Dave
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000307]
It is known that potassium channels are important for cell proliferation. HERG, a potassium channel protein, is a transmembrane protein, which increases in concentration on the cell surface of cancer cells. Apart from cancer cells, this protein is found only in the brain & heart tissue, in very low number. The proliferation of cells in cancer is dependent on activation of this protein, and it has been noted that blocking of this protein with drug molecule, helps inhibit the proliferation of the cells further. The current work aims to study the binding potentials of κ-PVIIA, conotoxin isolated from Conus purpurascens venom with HERG K+ channel of tumor cells, where HERG mutation has been noted. The toxin under consideration i.e. κ-conotoxins-PVIIA (κ-PVIIA) is a 27 residue peptide. The docking studies suggest that the conotoxin binds stably to the HERG protein. The study shows that the peptide interacts with the charged extracellular unit of the HERG protein, i.e. the extracellular portion of the S5 domain named S5-P extracellular linker. Study of binding of toxins of similar origin, with normal potassium channels has been studied in silico. Further, wet laboratory work needs to be conducted for development of a drug molecule from this toxin, to treat some number of cancers.
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A Review of QSAR studies to Discover New Drug-like Compounds Actives against Leishmaniasis and Trypanosomiasis
Juan Alberto Castillo-Garit, Concepción Abad, J. Enrique Rodríguez-Borges, Yovani Marrero-Ponce and Francisco Torrens
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000308]
The neglected tropical diseases (NTDs) affect more than one billion people (one-sixth of the world’s population) and occur primarily in undeveloped countries in sub-Saharan Africa, Asia, and Latin America. Available drugs for these diseases are decades old and present an important number of limitations, especially high toxicity and, more recently, the emergence of drug resistance. In the last decade several Quantitative Structure-Activity Relationship (QSAR) studies have been developed in order to identify new organic compounds with activity against the parasites responsible for these diseases, which are reviewed in this paper. The topics summarized in this work are: 1) QSAR studies to identify new organic compounds actives against Chaga’s disease; 2) Development of QSAR studies to discover new antileishmanial drusg; 3) Computational studies to identify new drug-like compounds against human African trypanosomiasis. Each topic include the general characteristics, epidemiology and chemotherapy of the disease as well as the main QSAR approaches to discovery/identification of new actives compounds for the corresponding neglected disease. The last section is devoted to a new approach know as multi-target QSAR models developed for antiparasitic drugs specifically those actives against trypanosomatid parasites. At present, as a result of these QSAR studies several promising compounds, active against these parasites, are been indentify. However, more efforts will be required in the future to develop more selective (specific) useful drugs.
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Freely accessible databases of commercial compounds for high-throughput virtual screenings
Arménio Jorge Moura Barbosa and Alberto Del Rio
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000309]
In the last decades computer-aided drug design techniques have been successfully used to guide the selection of new hit compounds with biological activity. These methods, that include a broad range of chemoinformatic and computational chemistry algorithms, are still discipline in full bloom. In particular, virtual screening procedures have celebrated a great popularity for the rapid and cost-effective assessment of large chemical libraries of commercial compounds. While the usage of in silico techniques promise an effective speed-up at the early-stage of the development of new active compounds, computational projects starting from scratch with raw chemical data are often associated with resource- and time-consuming preparation protocols, almost blunting the advantages of using these techniques. In order to help facing these difficulties, in the last years several chemoinformatic projects and tools have emerged in literature and have also been useful in preparing curated databases of chemical compounds for high-throughput virtual screening purposes. The review will focuses on the detailed analysis of free databases of commercial chemical compounds that are currently employed in virtual screening campaigns for drug design. The scope of this review is to compare such databases and suggest the reader on how and in which conditions the usage of these databases could be recommended.
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Recent advances on A3 adenosine receptor antagonists by QSAR tools
Feng Luan, Fernanda Borges and M. Natália D. S. Cordeiro
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000310]
Adenosine receptors (ARs) are widespread on virtually every human organ/tissue, and have long been considered promising therapeutic targets in a wide range of conditions, ranging from cerebral diseases to cancer, including inflammatory disorders. The knowledge acquired up to date in relation to ARs, in particular regarding the molecular biology of the A3 AR has provided a solid basis that led to the proposal of this receptor as a novel therapeutic target enabling the rational design and development of potent and selective A3 AR ligands. This review attempts to summarize the most recent developments in the A3 research field, focusing in particular on Quantitative Structure-Activity Relationships (QSAR) based studies that supported so far the design of new, potent and selective human A3 AR antagonists. In addition, a classical QSAR modeling study carried out on two series of pyrazolo-triazolopyrimidine derivatives is presented as a case study. Specifically, a systematic evaluation of linear and non-linear models along with a variety of structure representations and feature selection tools is reported. The combination of these techniques (neural networks to capture non-linear relationships in the data and feature selection to prevent over-fitting) was found to produce QSAR models with good overall accuracy and robustness, as well as predictivity on external data. Moreover, the study indicated that the antagonist activity of these derivatives is largely explained by electrostatic, steric and hydrogen-bonding factors, highlighting the role of the size, shape and type of inhibitor in forming effective blocking of the A3 AR subtype. The developed QSAR models could then be usefully employed to design new compounds selectively active towards the A3 adenosine receptor.
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Review of Synthesis, Biological assay, and QSAR studies of HMGR inhibitors
Isela García, Yagamare Fall Diop and Generosa Gómez
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000311]
Efficient drugs such as statins or mevinic acids are inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGR), an enzyme responsible for the double reduction of 3-hydroxy-3-methyl-glutaryl coenzyme A. These compounds promoted the synthesis and evaluation of new inhibitors for HMGR, named HMGRIs. The high number of possible candidates creates the necessity of Quantitative Structure-Activity Relationship models in order to guide the HMGRI (3-hydroxy-3-methyl-glutaryl coenzyme A inhibitor) synthesis. In this work, we revised different computational studies for a very large and heterogeneous series of HMGRIs. First, we revised QSAR studies with conceptual parameters how flexibility of rotation, probability of availability, etc; Next, using method of regression analysis; and QSAR studies in order to understand the essential structural requirement for binding with receptor. Next, we review 3D QSAR, CoMFA and CoMSIA with different compound to find out the structural requirements for 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibitory activity.
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Genomic Sequence Analysis of EGFR Regulation by MicroRNAs in Lung Cancer
Lawrence WC Chan and Feng F Wang
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000312]
Lung cancer is known as the top cancer killer in most developed countries. Epidermal growth factor receptor (EGFR) is frequently found to be activated by mutation or amplification in lung cancer. MicroRNA (miRNA) is a new class of small molecule that has emerged as important marker of lung cancer development and therapeutic target. There are queries on which miRNAs can regulate EGFR and it is important to predict the candidate miRNAs that targeting EGFR by bioinformatics and to investigate on the availability of these candidate miRNA regulators in lung cancer. Systematic and rigorous searches for miRNAs targeting EGFR were performed to 10 representative databases. The identified miRNAs that target EGFR were formulated into a conditional regulation matrix and then hierarchical clustering algorithm was applied for the analysis. The systematic search came up with 138 miRNAs that potentially target EGFR. Among them, 11 miRNAs including miR-7 and miR-128b were confirmed by published experimental data or literatures. There were 14 candidate miRNAs predicted by at least 3 prediction pipelines in this study which have never been previously reported to target EGFR. Further studies of these novel identified miRNAs may provide insight on the regulation of EGFR in lung cancer. To the best of our knowledge, this is the first bioinformatic study applying genomic sequence analysis for the prediction of miRNAs that target EGFR in lung cancer. This new strategy that integrates computational and published data approaches provides a fast and effective prediction of miRNAs in specific target genes involved in various diseases.
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From QSAR models of Drugs to Complex Networks: State-of-Art Review and Introduction of New Markov-Spectral Moments Indices
Pablo Riera-Fernández, Raquel Martín-Romalde, Francisco J Prado-Prado, Manuel Escobar Cristian R. Munteanu, Riccardo Concu, Aliuska Duardo-Sanchez and Humberto González-Díaz
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000313]
Quantitative Structure-Activity/Property Relationships (QSAR/QSPR) models have been largely used for different kind of problems in Medicinal Chemistry and other Biosciences as well. Nevertheless, the applications of QSAR models have been restricted to the study of small molecules in the past. In this context, many authors use molecular graphs, atoms (nodes) connected by chemical bonds (links) to represent and numerically characterize the molecular structure. On the other hand, Complex Networks are useful in solving problems in drug research and industry, developing mathematical representations of different systems. These systems move in a wide range from relatively simple graph representations of drug molecular structures (molecular graphs used in classic QSAR) to large systems. We can cite for instance, drug-target interaction networks, protein structure networks, protein interaction networks (PINs), or drug treatment in large geographical disease spreading networks. In any case, all complex networks have essentially the same components: nodes (atoms, drugs, proteins, microorganisms and/or parasites, geographical areas, drug policy legislations, etc.) and links (chemical bonds, drug-target interactions, drug-parasite treatment, drug use, etc.). Consequently, we can use the same type of numeric parameters called Topological Indices (TIs) to describe the connectivity patterns in all these kinds of Complex Networks despite the nature of the object they represent and use these TIs to develop QSAR/QSPR models beyond the classic frontiers of drugs small-sized molecules. Consequently, the goal of this work, in first instance, is offering a common background to all the manuscripts presented in this special issue. In so doing, we make a review of the most used software and databases, common types of QSAR/QSPR models, and complex networks involving drugs or their targets. In addition, we review both classic TIs that have been used to describe the molecular structure of drugs and/or larger complex networks. In second instance, we use for the first time a Markov chain model to generalize Spectral moments to higher order analogues coined here as the Stochastic Spectral Moments TIs of order k (πk). Last, we report by the first time different QSAR/QSPR models for different classes of networks found in drug research, nature, technology, and social-legal sciences using πk values. This work updates our previous reviews González-Díaz et al. Curr Top Med Chem. 2007; 7(10): 1015-29 and González-Díaz et al. Curr Top Med Chem. 2008; 8(18):1676-90. It has been prepared after kindly invitation of editor Prof. AB Reitz in commemoration of the 10th anniversary of this journal in 2010.
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Glutamatergic neurotransmission as molecular target of new anticonvulsants
Rosaria Gitto, Laura De Luca, Sara De Grazia and Alba Chimirri
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000315]
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) controlling physiological processes as learning and memory. However, the overactivation of glutamatergic neurotransmission is often related to various CNS chronic and acute diseases (epilepsy, ischaemia, Parkinson, etc.). This review will focus on the chemical structures, mechanism of action and main structure-activity relationships of anticonvulsant agents acting through glutamate neurotransmission.
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Recent Progress in Anticonvulsant Drug Research: Strategies for Anticonvulsant Drug Development and Applications of Antiepileptic Drugs for Non-Epileptic Central Nervous System Disorders
Sevim Dalkara and Arzu Karakurt
[Purchase Article] [BSP/CTMC/E-Pub/000316]
Major advances in antiepileptic drug therapy have been took place since 1950s. In the first period, several antiepileptic drugs (AEDs) such as phenobarbital, diphenylhydantoin, ethosuximide, carbamazepine, benzodiazepines and valproic acid were introduced to epilepsy treatment. After 1990 many new generation drugs (lamotrigine, topiramate, gabapentine, pregabaline, felbamate, lacosamide, levetiracetam etc.) have been developed. These novel AEDs have offered some advantages such as less side effects, fewer drug-drug interactions and better pharmacokinetic properties. But pharmacoresistance and therapeutic failure in 20-25% of the patients remain the main reasons to continue efforts to find safer and more efficacious drugs and ultimately a treatment for this devastating disease. Several AEDs especially novel compounds have been found to be effective also in the treatment of several other neurologic and psychiatric disorders. Chemical diversity of the newer antiepileptic drugs as well as those currently in clinical development is another point that encourages medicinal chemist to study this subject. This review summarizes recent studies on the development of potential anticonvulsant compounds in different chemical structures, their structure-activity relationships and also therapeutic usages of AEDs other than epilepsy.
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Targeting Oxidative Stress Component in the Therapeutics of Epilepsy
Faizul Azam, M.V.V. Prasad and Neelaveni Thangavel
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000317]
The role of free radical-mediated reactions in human neuropathology continues to attract significant interest. Oxidative injury produced by free radicals may play a role in the initiation and progression of epilepsy and, therapies aimed at reducing oxidative stress may ameliorate tissue damage and favorably alter the clinical course. The prevalence of epilepsy increases with age, and mitochondrial oxidative stress is a leading mechanism of aging and age-related degenerative disease, signifying a further involvement of mitochondrial dysfunction in seizure generation. Oxidative stress occurs when the generation of reactive oxygen species in a system exceeds the body's ability to neutralize and eliminate them, thus creating an imbalance or over abundance of free radicals. Therefore, it is imperative to maintain oxidative balance and control in the brain, and this is tightly regulated by antioxidants. In the last two decades, there has been an explosive interest in the role of antioxidants or neuroprotectants in clinical as well as experimental models of epilepsy. In this regard, the present review is intended to discuss the current state of knowledge pertaining to neuroprotection in epileptic conditions by employing diverse chemical agents including conventional as well as novel anti-epileptic drugs, and to highlight the efficacy of distinct neuroprotective strategies for preventing or treating epilepsy.
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An Insight into the New Anticonvulsant Agents
Waquar Ahsan, Mohsin M. Safhi, Nadeem Siddiqui, Shamama Javed, M Shamsher Alam, Bishmillah Azad and Jawaid Akhtar
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000318]
The use of current antiepileptic drugs has been questioned due to the nonselectivity of the drugs and the undesirable side effects posed by them. This led to an intensive investigation in this area worldwide during the past 10 years. There have been some significant outcomes and the findings are promising as far as drug efficacy and safety is concerned. This review covers the new anticonvulsant agents that have shown encouraging activities and less neurotoxicity. A detailed pharmacology and pathophysiology of different types of epilepsy is described here with the structural classification of most active agents. The new structural classes of compounds may prove as lead molecules and good candidates for the future investigations.
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Sodium Channel Blockers as Therapeutic Target for Treating Epilepsy: Recent Updates
Valentina Zuliani, Marco Fantini and Mirko Rivara
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000319]
The voltage-gated sodium channels (VGSCs) are a family of membrane proteins forming a pore, through which they selectively conduct sodium ions inward and outward cell’s plasma membranes in response to variations of membrane potentials, playing a fundamental role in controlling cellular excitability. Growing evidences suggest that abnormal VGSCs are involved in the pathophysiology of both acquired and inherited epilepsy. Approximately two dozen drugs are currently marketed for the treatment of epilepsy and most of them act as sodium channel blockers, preventing the return of the channels to the active state by stabilizing the inactive form. Despite the many drugs on the market, 30% of patients continue to experience seizures even in the presence of optimal doses of AEDs, while others continue to suffer from medication induced side effects. Thus, there is a great need to continue the search for new AEDs that are not only more effective, but also have a better side effects profile. For this reason, many efforts have been made in the recent years to identify new sodium channel blockers for the treatment of epilepsy. These studies have led to different classes of compounds, characterized by a great structural diversity.
The aim of this review is to provide an introduction on the structure and function of the sodium channels, followed by a brief historical perspective on the sodium channel blockers in use as anticonvulsant drugs. Moreover, it will focus on the medicinal chemistry of the sodium channel blockers recently published (2008-2011) and the drug designing/molecular modeling studies related to the receptor.
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Genome-wide expression analysis in epilepsy: a synthetic review
Abhay Sharma
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000320]
Synthesis of genome level expression data related to human epilepsy and animal models of epileptogenesis is a challenge because of differences in the use of animal species and strains, brain regions, methods to trigger epileptogenesis, tissue sampling time-points, epilepsy phenotype assessment, array platforms, normalization algorithms, cutoff points for identifying differentially expressed genes etc. Nevertheless, a comprehensive review of reported analysis identifies chemokine signaling and toll-like receptor signaling as convergent epileptogenic pathways. This transcriptomic evidence is supported by genome-wide association analysis in epilepsy, known effect of small molecules on gene expression, and cellular and molecular studies. The present review thus demonstrates that synthesis of diverse genome level expression analysis in complex brain disorders can identify promising leads in understanding the mechanisms underlying them.
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Recent Advances in Positron Emission Tomography (PET) Radiotracers for Imaging Phosphodiesterases
José Ignacio Andrés, Meri De Angelis, Jesús Alcázar, Sofie Celen and Guy Bormans
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000321]
Phosphodiesterases (PDEs) are a family of enzymes that metabolically inactivate the second messengers 3’,5’-cyclic adenosine monophosphate (cAMP) and/or 3’,5’-cyclic guanosine monophosphate (cGMP). These two messengers regulate the extracellular signal from the plasma membrane G protein-coupled receptors (GPCRs) to the intracellular effector proteins, hence modulating a wide variety of biological processes both in the central nervous system (CNS) and peripheral tissues. Although there are many radiotracers available for positron emission tomography (PET) studies of different receptors, there are just a few tracers available for imaging studies of second messenger systems. The first reported PDE PET ligands were the 11C-labeled versions of the PDE4 inhibitors rolipram and Ro 20-1724, and, to date, PET imaging studies in human subjects have only been reported with [11C]rolipram. As a consequence of the growing interest in identifying selective PDE inhibitors as potential new therapeutic agents, new PET radiotracers for imaging specific PDEs have been described in literature as well. This article highlights these efforts on the design and evaluation of novel PET radioligands for in vivo imaging of PDEs.
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A Novel Method for Determination of Drug Distribution in Rat Brain Tissue Sections by LC/MS/MS: Functional Tissue Microanalysis
John A. Masucci, Andrew D. Mahan, Joseph D. Kwasnoski and Gary W. Caldwell
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000322]
Determination of drug distribution in brain and other tissues is important in pharmaceutical research. Tissue drug levels need to be determined routinely as they are usually diagnostic for both efficacy and toxicity. Determination of tissue levels in small organ subregions is frequently performed due to important functional considerations. These measurements have traditionally been very tedious requiring extensive dissection and specimen pooling to achieve detection of analytes of interest. Direct and indirect methods utilizing mass spectrometry have been reported for detection of analytes in tissue specimens. Typically, these require very specialized MS or sampling equipment and are only partially successful due to analyte response. We have developed a novel approach for quantitation of tissue sections called Functional Tissue Microanalysis (FTM) in which small circular samples are removed from subregions of interest, extracted and analyzed by conventional LC/MS/MS utilizing electrospray ionization. This allows direct measurement of regional concentrations without dissection and homogenization of tissue specimens as many subregions can be sampled from a single mounted section. Utilization of the FTM approach for analysis of both sagittal and coronal rat brain sections is shown for quantitation of raclopride and rimonabant. Reproducibility of this approach and comparison to conventional methods is reported.
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Screening Strategy for Chiral and Achiral Separations in Supercritical Fluid Chromatography Mode
David Speybrouck, David Corens and Jean-Michel Argoullon
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000323]
Supercritical fluid (SF) was discovered 200 years ago, but the use of this fluid as a mobile phase in chromatography only became popular fifty years ago. The development of the supercritical fluid chromatography (SFC) was progressing slowly due to technological problems since ten years; the interest for this chromatographic mode has been growing up as the construction of the SFC instruments is more or less similar with HPLC instruments. The main difference in SFC is the installation of a back pressure regulator which is implemented to control the pressure above the critical pressure. SFC is widely used in chiral chromatography where Polysaccharide phases are the most versatile in use. The mobile phase is mainly composed by CO2 but the polarity can be increased by adding alcohol. The nature of the alcohol can change drastically the selectivity. The choice of the best tandem stationary phase / mobile phase is difficult to predict. Hence a full screening with different stationary phases and mobile phase solvents is often mandatory. For the achiral separation, SFC is more and more used. Achiral SFC can be classified as normal phase mode, it means that stationary phases are more polar than mobile phase and retention times decrease as polarity of the mobile phase increases. Most popular stationary phases are silica linked with polar group such as aminopropyl, cyanoprpyl, diol or 2-ethylpyridine. Mobile phase are generally composed by CO2 and methanol. SFC can be used as a complementary technique for reversed phase HPLC or sometimes even to replace HPLC.
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Chromatographic Separation of Bioactive Oxycholesterols by GC, HPLC and SFC
Heather McAllister and Jiejun Wu
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000324]
In this paper we report the development of chromatographic methods for the separation of 8 biologically active hydroxycholesterols (OHC’s) which include the single-hydroxyl addition species 7α-OHC, 7α-OHC, 25-OHC and 27-OHC, together with the double-hydroxyl addition species 7α, 25-OHC, 7ß, 25-OHC, 7α, 27-OHC, and 7ß, 27-OHC. Four complementary techniques were employed (gas chromatography, normal phase and reversed phase high performance liquid chromatography, and supercritical fluid chromatography), and for each of the techniques, an optimized method for the separation of all eight compounds in a mixture is presented.
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Insights from Structural Analysis of cFMS/Inhibitor Complexes: Common Interactions via Three Structurally Dissimilar Scaffolds
Renee L. DesJarlais
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000325]
A small-molecule drug discovery effort can benefit from having several chemical series. Where multiple series are not available, it is often the goal of a project to find novel scaffolds. Structural studies of ligand/protein complexes provide important information on the interactions driving binding. By generalizing these, it is possible to find molecules lacking in similarity in their connectivity yet retaining the ability to interact with the same target protein. Our studies on inhibitors of the cFMS tyrosine kinase provide a dramatic example of three different chemical series that make the same key interactions with the target protein. Collectively these structural data provide a striking example of the pharmacophore hypothesis at work. In addition, they should prompt one to employ a broad approach when attempting scaffold hopping or any search for a novel series. It is clear that molecules that bind with similar interactions to a target need not possess 2-dimensional molecular similarity.
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The IC50 Concept Revisiteds
Gary W. Caldwell, Zhengyin Yan, Wensheng Lang and John A. Masucci
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000326]
A major strategy used in drug design is the inhibition of enzyme activity. The ability to accurately measure the concentration of the inhibitor which is required to inhibit a given biological or biochemical function by half is extremely important in ranking compounds. Since the concept of the half maximal inhibitory concentration (IC50) is used extensively for studying reversible inhibition enzymatic reactions, it is important to clearly understand the experimental design and the mathematical modeling techniques used to generate IC50 values. The most important part of the experimental design is to measure the rate of production of [P] during the linear phase of the time course of the reaction and to prove that the enzyme-catalyzed reaction is reversible. The most important part of the mathematical modeling is to select the correct model and to have a firm understanding on how to handle outliers in the data. These topics are discussed in greater detail along with a discussion on how much quantitative and mechanistic information can be reasonably deduced from an experiment.
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The Current Status of Time Dependent CYP Inhibition Assay and In Silico Drug-drug Interaction Predictions
Zhengyin Yan and Gary W. Caldwell
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000327]
Various CYP time-dependent inhibition (TDI) assays have been widely implemented in drug discovery and development which has led to great success in positively identifying compounds with mechanism-base inhibition liability. However, drug-drug interaction (DDI) predictions by various in-silico models utilizing kinetic parameters obtained from TDI assays have met with significant challenges including questionable kinetic data, over-simplified in-vitro models and unreliable mathematic algorithms. Although significant efforts have been made to standardize the TDI assay and refine mathematical models, recent evaluation studies have revealed that the kinetic parameters of TDI, the most important in-vitro data required by all DDI prediction models, are significantly impacted by a variety of experimental variables including microsomal protein concentration, metabolic stability, CYP-specific probes, and post-incubation time. This review attempts to provide medicinal chemists a brief overview on the current status of TDI assays, determination of kinetic parameters and in silico DDI predictions with emphasis on the complexity of the TDI kinetics and limitations of current in-vitro models and DDI prediction methodologies.
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Small Molecule Compound Logistics Outsourcing – Going beyond the “Thought Experiment”
Devon L. Ramsay, Joseph D. Kwasnoski and Gary W. Caldwell
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000328]
Increasing pressure on the pharmaceutical industry to reduce cost and focus internal resources on “high value” activities is driving a trend to outsource traditionally “in-house” drug discovery activities. Compound collections are typically viewed as drug discovery’s “crown jewels”; however, in late 2007, Johnson & Johnson Pharmaceutical Research & Development (J&J PRD) took a bold step to move their entire North American compound inventory and processing capability to an external third party vendor. The authors discuss the combination model implemented, that of local compound logistics site support with an outsourced centralized processing center. Some of the lessons learned over the past five years were predictable while others were unexpected. The substantial cost savings, improved local service response and flexible platform to adjust to changing business needs resulted. Continued sustainable success relies heavily upon maintaining internal headcount dedicated to vendor management, an open collaboration approach and a solid information technology infrastructure with complete transparency and visibility.
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An Integrated Data Management Framework for Drug Discovery – From Data Capturing to Decision Support
Walter Cedeño, Simson Alex, Edward P. Jaeger, Dimitris Agrafiotis and Victor Lobanov
[FULL-TEXT INQUIRY] [BSP/CTMC/E-Pub/000329]
Drug discovery is a highly complex process requiring scientists from wide-ranging disciplines to work together in a well-coordinated and streamlined fashion. While the process can be compartmentalized into well-defined functional domains, the success of the entire enterprise rests on the ability to exchange data conveniently between these domains, and integrate it in meaningful ways to support the design, execution and interpretation of experiments aimed at optimizing the efficacy and safety of new drugs. This, in turn, requires information management systems that can support many different types of scientific technologies generating data of imposing complexity, diversity and volume. Here, we describe the key components of our Advanced Biological and Chemical Discovery (ABCD), a software platform designed at Johnson & Johnson to bring coherence in the way discovery data is collected, annotated, organized, integrated, mined and visualized. Unlike the Gordian knot of one-off solutions built to serve a single purpose for a single set of users that one typically encounters in the pharmaceutical industry, we sought to develop a framework that could be extended and leveraged across different application domains, and offer a consistent user experience marked by superior performance and usability. In this work, several major components of ABCD are highlighted, ranging from operational subsystems for managing reagents, reactions, compounds, and assays, to advanced data mining and visualization tools for SAR analysis and interpretation. All these capabilities are delivered through a common application front-end called Third Dimension Explorer (3DX), a modular, multifunctional and extensible platform designed to be the “Swiss-army knife” of the discovery scientist.
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