Frontiers in Drug Design and Discovery

Prostate cancer (CaP) is the most frequently diagnosed cancer among men and the second leading cause of cancer death for men in both economically developed and developing countries. CaP is usually diagnosed at an early stage with prostate biopsy, following a screening test showing elevated serum levels of prostate-specific antigen (PSA) and/or a positive digital rectal examination. Early CaP diagnosis is the main cause for the significant decrease of metastatic cases, observed during the last twenty years. On the other hand, the wide use of the PSA screening test led also to CaP overdiagnosis and overtreatment. Because of the large variation of CaP characteristics and clinicopathological features, accurate prognosis of CaP patients is a very important issue that determines treatment options. In this chapter, we review the most promising prognostic CaP biomarkers that have been suggested so far. In the emerging era of personalized medicine, these CaP biomarkers could be exploited in the clinics to increase CaP patients’ survival and quality of life.

Due to the continuous burden of cancer, an extensive research on the factors responsible for an increase in cancer cases and its effective curative measures are utmost essential. Cancer has the potential to resist drug activity resulting in limited chemotherapeutic effectiveness, which leads to mortality in most of the cases. Drug resistance creates a major hurdle in cancer therapy research and can be classified as intrinsic and acquired resistance. Factors which are responsible for developing the resistance are generally present in the oncogenic cells even before chemotherapy, in case of intrinsic resistance, whereas acquired resistance develops during or after chemotherapeutic treatment. Chemoresistance in cancerous cells can be comprehensively ascribed to genetic factors, epigenetic changes as well as tumor microenvironment. This chapter aims to provide a paradigm to understand the factors and mechanisms underlying the cause of resistance to cancer chemotherapeutic drugs. Also, recent strategies to overcome chemoresistance along with novel interventions involving the understanding of molecular signatures of cancer, chemoresistance biomarkers and companion diagnostics have been reviewed. Knowledge thus gained would benefit us in developing effective strategies to help us overcome the burden of chemoresistance in cancerous cells.

Human genome sequencing project has tremendously contributed towards the identification of GPCRs and orphan GPCRs. Currently, more than 800 GPCRs and orphan GPCRs are known. The exploration of the mechanism of the signalling pathways is imperative to understand various roles of these GPCRs, particularly orphan GPCRs. The characterization of physiological functions of orphan GPCRs through development of knockout mice has been a successful method. However, designing and development of novel molecules as agonist or antagonist, having higher efficacy, potency and better safety profile, requires consideration of a more dynamic, multipath way system that a drug can take to exert an effect. Most recently, synthetic circuits have become an important feature of electronic service delivery within the modern life science field, demanding close attention to their functionality, sustainability and usability. Some researchers have begun to examine the functionality of synthetic circuits but there is no relevant work done on software designing related to this specific field which will help to build a comprehensive model for regulatory system. The major objective of system biology is to identify all molecules and their interactions within a living cell. The knowledge about these molecules and the intermolecular interactions is critical to determine the function of human physiological system. The de novo engineering of genetic circuits, biological modules and synthetic pathways is a step towards understanding the biological machinery. The construction of genetic circuits involves proteins as input nodes (receptors), bowires (repressors and activators), or output nodes (enzymes and signaling) to the system. The intrinsic complexity of the proteins makes it difficult to correlate their sequence, structure, functions and interactions. Switching biology deals with redesigning natural proteins or designing novel proteins. An insight into the role of GPCR, its multiple interactions with other proteins, gene and other biomolecules is essential in order to design and develop better therapeutic intervention. An integrated approach combining structure based drug design, systems biology and biological circuits can help in gaining synergy in drug design. The chapter highlights the role of systems biology and biological circuits in drug discovery.

Discovered 45 years ago, ribavirin still proves useful as a broad-spectrum anti-viral drug against different RNA and DNA viruses. Although many cellular and molecular mechanisms of ribavirin action have been proposed during several decades of the extensive research, the complete spectrum of its actions is still not fully known. The direct mechanisms of ribavirin anti-viral action involve RNA polymerase inhibition and lethal mutagenesis. The main intracellular target of ribavirin action is inosine 5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in a de novo synthesis of guanine nucleotides. The inhibition of IMPDH activity leads to depletion of the guanine nucleotide pool and the consequent attenuation of GTPdependent cellular processes, inducing cell cycle arrest, and the interruption of DNA and RNA synthesis. Since these processes are essential for the normal as well as mitogenic functions of all cells, the inhibition of IMPDH probably represents the central mechanism of ribavirin action, including its cytotoxic effect. Recent data suggest that ribavirin may also be effective as an anti-cancer drug. By inhibiting the eukaryotic translation initiation factor e4E (eIF4E), ribavirin impedes eIF4E-mediated oncogenic transformation. Additionally, immunomodulatory and immunosuppressive actions of ribavirin have been shown in different in vivo and in vitro models of neuroinflammation. Accumulating evidence points to important cell type-specific differences in response to ribavirin that may arise from cell specific variations in ribavirin metabolism, as well as the functional status of targeted cells. This chapter reviews the antiviral, anticancer and anti-inflammatory activities of ribavirin and its metabolites, and discusses the possible mechanisms of action.

Carbon nanotubes (CNTs), a carbon allotrope with various physicochemical properties, have gained worldwide interest since last two decades. CNTs are made up of cylindrical shaped graphene foils with nanometric dimension and several micrometres in length. The application of CNTs in the field of pharmacy and medicine is based on their large surface area capable to adsorb or conjugate various classes of drugs, genes, vaccines, and antibodies. This review focuses on the applicability of CNTs as targeted drug delivery vehicle considering the biopharmaceutics and toxicokinetics including advantages, obstacles, and perspectives of various CNTs.

When the structure of tautomycin (TM) was determined, it was pointed out that the molecule must have potent inhibitory effects against protein phosphatases (PPs). The hint was brought from the structure of okadaic acid (OA), which was just disclosed to be a potent inhibitor of PPs. Protein phosphatase type 2A (PP2A) was the primary molecular target of OA, while TM was found to be a dual inhibitor for protein phosphatase type 1 (PP1) and PP2A, with partial selectivity to PP1. The rigid structure of OA, however, exhibited the biological activity as a tumor promoter, whereas the flexible structure of TM did not induce any tumor promotion in vivo. Tautomycetin (TC), having very similar structure to TM, was found to be the only inhibitor specific to PP1 at low concentrations, and the discovery opened the door to therapeutic strategies for immune disorders, cancer or neurological disorders involving PP1 and to understanding the distinguishable roles of PP1 and PP2A, two major Ser/Thr PPs in human cells. Sephin1, a selective inhibitor of PP1 holoenzyme containing growth arrest and DNA damage-inducible protein (GADD34), attenuated expression of stressinducible gene products. The approach was one of the several challenges for developing PP1-targeted therapeutics for neurological disorders to which circadian rhythm would be related. Thus appropriately modulating PP1 activity could lead to new treatments for neurological disorders in Minkowski space, a combination of threedimensional space and one dimension of time.

Airway diseases associated with inflammation and airway obstruction are known for an accumulation of inflammatory blood cells in the lung tissue and airways and for a typical inflammatory symptomatology. An increased leak of inflammatory cells into the target tissue and their activation prolong the survival of pro-inflammatory cells. The complex cell interactions in the airways play an important role in the development of chronic inflammation, e.g. in bronchial asthma (BA). The inflammation in BA is directed by the activation of Th2 lymphocytes that produce various inflammatory cytokines (interleukins IL-4, IL-13, and IL-5), eotaxin etc. In chronic obstructive pulmonary disease (COPD), an involvement of alveolar macrophages and neutrophils with the release of IL-8, neutrophil elastase, tumor necrosis factor (TNF)-α and myeloperoxidase has been confirmed. Currently, 11 families of PDEs are known. In contrast to non-selective PDE inhibitors (e.g. theophylline), selective PDE inhibitors are able to act with a significantly reduced risk of adverse effects. Several groups of selective PDE inhibitors, i.e. PDE3, PDE4, PDE5, and PDE7, exert a possible relationship to immune responses in the airways. The activity of PDE3 in the airways has been confirmed in alveolar macrophages, endothelial cells, platelets and airway smooth muscle. Simultaneous administration of siguazodan (PDE3 inhibitor) and rolipram (PDE4 inhibitor) has led to enhanced relaxing response, suggesting a synergism and potential benefit in parallel inhibition of PDE3 and PDE4. The PDE4 enzyme family is expressed in various inflammatory cells; therefore, its inhibition has shown anti-inflammatory and immunomodulating effects. Rolipram suppresses neutrophil- and eosinophil-mediated inflammation, secretion of interleukins and activation of pro-inflammatory cells. Agents from the second generation of PDE4 inhibitors (e.g. roflumilast approved for clinical use in COPD patients) are able to suppress airway hyperresponsiveness, release of TNF-α, fibrotisation and remodeling of the lung parenchyma. An inhibition of PDE7 can contribute to anti-inflammatory action as its expression has been confirmed in T-cells, epithelial cells, airway and vascular smooth muscle cells, lung fibroblasts, and eosinophils. While their effectiveness in individual administration is relatively weak, the simultaneous PDE4 and PDE7 inhibition seems to be promising. The antiinflammatory activity of dual PDE inhibitors (e.g. PDE3/PDE4, or PDE4/PDE7) has been studied only in COPD conditions, and only in limited extent in allergic BA. An inhibition of PDE5 leads to decreased pulmonary vascular resistance, suppressed pulmonary hypertension and vascular remodeling. Sildenafil (PDE5 inhibitor) inhibits cell proliferation, has pro-apoptotic action, and suppresses the bronchial hyperresponsiveness, infiltration by white blood cells, and concentrations of exhaled NO. These findings suggest the possible benefits of combining the PDE4 and PDE5 inhibitors in the therapy of BA and COPD. There are several studies with roflumilast and cilomilast already conducted in patients with BA; however, there is a lack of relevant data from experimental and clinical studies on simultaneous effects of PDE4 and PDE5, PDE3 and PDE4, and PDE4 and PDE7 up to now. Acute lung injury (ALI) represents another disorder often associated with the inflammatory changes. ALI arises from various reasons: a direct injury to the lungs by aspiration of the gastric content, by aspiration of neonatal meconium, by pneumonia, or by inhalation of toxic gases. In addition, ALI is generated indirectly as a consequence of serious systemic injury, e.g. in sepsis, severe trauma with shock, or pancreatitis. These situations may progress into a more severe form of ALI, acute respiratory distress syndrome (ARDS). Several PDE inhibitors, including non-selective PDE inhibitor aminophylline, have been used in various animal models of ALI/ARDS. In experiments, the selective PDE3, PDE4, and PDE5 inhibitors have demonstrated potent anti-inflammatory, anti-oxidative, anti-edematous and vasodilation effects associated with lower occurrence of side effects than observed with non-selective PDE inhibitors, as their influence is limited to one type of PDE only. However, their use in these disorders is still under research.