Current Pharmaceutical Design
Volume 17, Number 17, June 2011

Structural Basis of Agonist Selectivity for Different nAChR Subtypes: Insights from Crystal Structures, Mutation Experiments and Molecular Simulations Pp.1652-1662 Ruo-Xu Gu, Yu-Qing Zhong and Dong-Qing Wei [View Abstract] [Purchase Article]

Nicotinic acetylcholine receptors (nAChRs) are members of ligand gated ion channels (LGICs) which transduce chemical signal into electrical signal in neuron and neuromuscular junction. They are pentamerics which contain an extra-cellular domain (also known as ligand binding domain or LBD), a trans-membrane domain and a cytoplasmic domain (intra-cellular domain). Agonist binding to the extra-cellular domain invokes positive ion flux as well as action potential in neurons, muscle cells and endocrine cells whereas antagonist binding inhibits ion flux. There are various endogenous or exogenous compounds which behave as agonists or antagonists targeting nAChRs. During the last decades, the whole structure of muscle type nAChR as well as the crystal structures of acetylcholine-binding proteins (AChBPs) which are homologues of the nAChRs extra-cellular domain has been obtained. These structures, together with other studies including mutation experiments and molecular simulations, provide insights into both of the nAChR architecture and its agonist binding cavity. Our review gives detailed accounts of the recent progresses in order to gain insights into agonist selectivity for different nAChR subtypes.

Molecular Recognition in the Case of Flexible Targets Pp.1663-1671 Anthony Ivetac and J. Andrew McCammon [View Abstract] [Purchase Article]

A protein's flexibility is well recognized to underlie its capacity to engage in critical functions, such as signal transduction, biomolecular transport and biochemical reactivity. Molecular recognition is also tightly linked to the dynamics of the binding partners, yet protein flexibility has largely been ignored by the growing field of structure-based drug design (SBDD). In combination with experimentally determined structures, a number of computational methods have been proposed to model protein movements, which may be important for small molecule binding. Such techniques have the ability to expose new binding site conformations, which may in turn recognize and lead to the discovery of more potent and selective drugs through molecular docking. In this article, we discuss various methods and focus on the Relaxed Complex Scheme (RCS), which uses Molecular Dynamics (MD) simulations to model full protein flexibility and enhance virtual screening programmes. We review practical applications of the RCS and use a recent study of the HIV-1 reverse transcriptase to illustrate the various phases of the scheme. We also discuss some encouraging developments, aimed at addressing current weaknesses of the RCS.

Structural and Molecular Basis of Carbohydrate-Protein Interaction Systems as Potential Therapeutic Targets Pp.1672-1684 Yukiko Kamiya, Maho Yagi-Utsumi, Hirokazu Yagi and Koichi Kato [View Abstract] [Open Access Plus Article]

The sugar chains covalently modifying proteins and lipids are recognized by a variety of proteins, thereby mediating a broad range of physiological and pathological events on cell surfaces as well as in cells. Hence, these carbohydrate – protein interaction systems could be potential therapeutic targets for various diseases, including viral infections, autoimmune diseases and neurodegenerative disorders. Cumulative crystallographic data of lectins complexed with their cognate carbohydrate ligands have elucidated the sugar recognition modes of these proteins, offering a structural basis for the design of drugs targeting carbohydrate – lectin interaction systems. In particular, structural and functional studies of animal L-type lectins, which possess a carbohydrate recognition domain with a structural resemblance to that of leguminous lectins such as concanavalin A, have demonstrated the molecular mechanisms underlying their distinct roles in sorting and trafficking of glycoproteins in cells, exemplifying the structure-based engineering that manipulates the sugar-binding properties of lectins. Furthermore, structural basis has been provided for the functional interplay between the L-type lectin ERGIC-53 and the EF-hand Ca2+-binding protein MCFD2 in the intracellular transport of the coagulation factors V and VIII. This article also deals with pathological carbohydrate – protein interactions involving ganglioside clusters on cell surfaces, particularly focusing on the interaction between amyloid β (Aβ) and GM1 ganglioside. This interaction triggers conformational transition and consequent aggregation of Aβ, and therefore, is considered to be a key step in Alzheimer's disease. The recently reported structural information of the Aβ – GM1 interaction is presented, underscoring the significance of assemblages of glycoconjugates as therapeutic targets.

A Novel Ligand-Mapping Method Based on Molecular Liquid Theory Pp.1685-1694 Takashi Imai [View Abstract] [Purchase Article]

The recent development of a novel ligand-mapping method is reviewed. The method is based on a statistical-mechanical molecular theory of solvation, known as the three-dimensional reference interaction site model (3D-RISM). In the 3D-RISM-based ligand mapping (3D-RISM-LM) method, using the all-atom model for a target protein immersed in a ligand-water mixture solvent, the 3D-spatial distributions of the ligand atomic sites around the protein are first obtained, and then the most probable binding modes of the ligand molecule are constructed from the distributions. Unlike conventional docking simulations, 3D-RISM-LM can incorporate the effect of water from the atomic to thermodynamic level into the binding affinity through statistical mechanics. It has been demonstrated that 3D-RISM-LM can sensitively detect even weak binding modes of small molecules over the entire surface of protein. Therefore, this approach is expected to be particularly useful in fragment-based drug design.

In Silico Screening of Bioactive and Biomimetic Solutes Using Molecular Integral Equation Theory Pp.1695-1708 David S. Palmer, Gennady N. Chuev, Ekaterina L. Ratkova and Maxim V. Fedorov [View Abstract] [Purchase Article]

The Integral Equation Theory (IET) of Molecular Liquids is a theoretical framework for modelling solution phase behaviour that has recently found new applications in computational drug design. IET allows calculation of solvation thermodynamic parameters at significantly lower computational expense than explicit solvent simulations, but also provides information about the microscopic solvent structure that is not accessible by implicit continuum models. In this review we focus on recent advances in two fields of research using these methods: (i) calculation of the hydration free energies of bioactive molecules; (ii) modelling the aggregation of biomimetic molecules. In addition, we discuss sources of experimental solvation data for druglike molecules.

Membrane Targeted Chemotherapy with Hybrid Liposomes for Tumor Cells Leading to Apoptosis Pp.1709-1719 Ryuichi Ueoka, Yoko Matsumoto, Koichi Goto, Hideaki Ichihara and Yuji Komizu [View Abstract] [Purchase Article]

We have produced hybrid liposomes (HL) which can be prepared by sonication of a mixture of vesicular and micellar molecules in a buffer solution. The physical properties of HL such as size, shape, and membrane fluidity can be controlled by changing the constituents and compositional ratio. We have employed HL for chemotherapy and interesting results are as follows; (A) The uniform and stable structure of HL composed of L-α-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylenedodecyl ether (C12(EO)n) with a diameter of 80 nm was revealed. (B) The remarkable inhibitory effects of HL on the growth of various tumor cells were attained in vitro. (C) Induction of apoptosis by HL was obtained and the pathway of apoptosis induced by HL was clarified. (D) A good correlation between the membrane fluidity of HL and inhibitory effects of HL for tumor cells was obtained. (E) Significantly chemotherapeutic effects were obtained using mice model of carcinoma after the treatment with HL without any side effects in vivo. (F) In clinical applications, prolonged survival and remarkable reduction of neoplasm were attained in patients with lymphoma after the treatment with HL without any side effects after the approval of the bioethics committee.

Computational Studies of Influenza A Virus at Three Important Targets: Hemagglutinin, Neuraminidase and M2 Protein Pp.1720-1739 Thanyada Rungrotmongkol, Pathumwadee Yotmanee, Nadtanet Nunthaboot and Supot Hannongbua [View Abstract] [Purchase Article]

While the seasonal influenza viruses spreading around the world cause the annual epidemics, the recent outbreaks of influenza A virus subtype H5N1 and pandemic H1N1 have raised global human health concerns. In this review, the applicabilities of computational techniques focused on three important targets in the viral life cycle: hemagglutinin, neuraminidase and M2 proton channel are summarized. Protein mechanism of action, substrate binding specificity and drug resistance, ligand-target interactions of substrate/ inhibitor binding to these three proteins either wild-type or mutant strains are discussed and compared. Advances on the novel antiinfluenza agents designed specifically to combat the avian H5N1 and pandemic H1N1 viruses are introduced. A better understanding of molecular inhibition and source of drug resistance as well as a set of newly designed compounds is greatly useful as a rotational guide for synthetic and medicinal chemists to develop a new generation of anti-influenza drugs.

Molecular Recognition Explored by a Statistical-Mechanics Theory of Liquids Pp.1740-1757 Saree Phongphanphanee, Norio Yoshida and Fumio Hirata [View Abstract] [Purchase Article]

“Molecular recognition” is one of the most important molecular processes for living systems in order to maintain their life, since most of the biological functions are initiated with the process. Understanding of the process is also important for designing a new drug. Firstly, it is important to find a target of a drug, which is in many cases a function of protein or DNA to be inhibited. Secondly, binding a drug molecule to the active site of a biomolecule itself is a “molecular recognition process. In the present article, we review our recent studies on the molecular recognition process, carried out by means of the 3D-RISM theory, a statistical mechanics theory of liquids. Studies on the conduction mechanisms in two types of molecular channels, aquaporin and the M2 channels, are reviewed.

Drug Design by Generalized-Ensemble Simulations Pp.1758-1772 Yuko Okamoto [View Abstract] [Purchase Article]

In pharmaceutical design based on molecular simulations, one faces a great difficulty. Conventional simulations in the canonical ensemble are of little use, because they tend to get trapped in some of the local-minimum-energy states that exist in a huge number. A simulation in generalized ensemble performs a random walk in potential energy space and can overcome this difficulty. In this article we review a few of powerful generalized-ensemble algorithms, namely, replica-exchange method, multidimensional replica- exchange method, and replica-exchange umbrella sampling. The effectiveness of the methods is tested with ligand and short peptide systems.