Naphthyridinomycin-DNA adducts: a molecular modeling study

Monocovalent groove binding complexes of antitumor antibiotic naphthyridinomycin and its analogs with DNA sequence d(ATGCAT)2 have been studied by molecular mechanics to understand which enantiomer of the drug and what chirality at C(7) of the drug are preferred for forming better drug-DNA adducts. The effect of hydroquinone intermediate and the substitution at C(11) on drug-DNA interactions have also been investigated. The results indicate that the enantiomer that forms the best adduct is different from the one reported earlier in the literature. The drug with an R configuration at C(7) is preferred for binding. The hydroquinone models do not necessarily provide a given analog of the drug with additional favorable DNA interactions. The substitution at C(11) by OH provides the best binding model. This finding agrees well with the results from previous biochemical studies. The sequence specific studies indicate that the sequence d(ATGCAT)2 is slightly preferred over others.     

Interaction of d-tubocurarine with potassium channels: molecular modeling and ligand binding

Potassium channels play fundamental roles in physiology. Chemically diverse drugs bind in the pore region of K+ channels. Here, we homology-modeled voltage- and Ca2+-gated K+ channel BK and voltage-gated Kv1.3 using the X-ray structures of MthK and Kv1.2, respectively, and simulated the binding of d-tubocurarine in the inner pore of the channels. Monte Carlo minimization predicted that d-tubocurarine can bind in the open pore of both channels with its long axis parallel to the pore axis. The cationic groups of d-tubocurarine can displace K+ from the ion dehydration site at the selectivity filter. The predicted binding energy of d-tubocurarine in Kv1.3 is less preferable than in BK. To test this prediction, the currents through Kv1.3 and BK channels were measured in the absence and presence of d-tubocurarine. Results show that d-tubocurarine blocks current through Kv1.3 when applied from either side of the membrane only in millimolar concentrations (Kd= 1 mM), whereas half-blocking concentrations of the internally applied d-tubocurarine to BK are as low as approximately 8 microM. This indicates that the affinities of both external and internal d-tubocurarine to Kv1.3 are much lower than those to BK channels. Our study reveals the K+ dehydration site as a determinant of the d-tubocurarine receptor, predicts binding modes of d-tubocurarine in K+ channels, and suggests that the open pore in BK is wider than in Kv1.3. The results imply that MthK can be used for homology modeling of the pore region of channels activated by forces applied to the inner helices.     

Immunomodulator structure-activity relationships: contribution of molecular modeling

Molecular modeling used to compare 64 immunostimulant compounds with pyrrolie quinolein or purine nuclei has pointed out that a common spatial structure is found in most of the active compounds. An additional study of immunostimulants (levamisole, muramyldipeptide) or immunosuppressive molecules (rapamycin) was performed. A common pharmacophore was found on every studied compound. It was composed of three neighboring electroattractive atoms and a further fourth atom. The favorable conformation of rapamycin for immunosuppressive action, which is not the more stable conformation, could explain the loss of its activity, or those of related macrolides, when some minor chemical modifications are tested. These findings validate the proposed concept and provide a view of the mechanism of action of most of the immunomodulator compounds for preparing novel compounds     

Understanding the molecular basis of HBV drug resistance by molecular modeling

Despite the significant successes in the area of anti-HBV agents, resistance and cross-resistance against available therapeutics are the major hurdles in drug discovery. The present investigation is to understand the molecular basis of drug resistance conferred by the B and C domain mutations of HBV-polymerase on the binding affinity of five anti-HBV agents [lamivudine (3TC, 1), adefovir (ADV, 2), entecavir (ETV, 3), telbivudine (LdT, 4) and clevudine (l-FMAU, 5)]. In this regard, homology modeled structure of HBV-polymerase was used for minimization, conformational search and induced fit docking followed by binding energy calculation on wild-type as well as on mutant HBV-polymerases (L180M, M204V, M204I, L180M + M204V, L180M − M204I). Our studies suggest a significant correlation between the fold resistances and the binding affinity of anti-HBV nucleosides. The binding mode studies reveals that the domain C residue M204 is closely associated with sugar/pseudosugar ring positioning in the active site. The positioning of oxathiolane ring of 3TC (1) is plausible due the induced fit orientation of the M204 residue in wild-type, and further mutation of M204 to V204 or I204 reduces the final binding affinity which leads to the drug resistance. The domain B residue L180 is not directly close (∼6 Å) to the nucleoside/nucleoside analogs, but indirectly associated with other active-site hydrophobic residues such as A87, F88, P177 and M204. These five hydrophobic residues can directly affect on the incoming nucleoside analogs in terms of its association and interaction that can alter the final binding affinity. There was no sugar ring shifting observed in the case of adefovir (2) and entecavir (3), and the position of sugar ring of 2 and 3 is found similar to the sugar position of natural substrate dATP and dGTP, respectively. The exocyclic double bond of entecavir (3) occupied in the backside hydrophobic pocket (made by residues A87, F88, P177, L180 and M204), which enhances the overall binding affinity. The active site binding of LdT (4) and l-FMAU (5) showed backward shifting along with upward movement without enforcing M204 residue and this significant different binding mode makes these molecules as polymerase inhibitors, without being incorporated into the growing HBV-DNA chain. Structural results conferred by these l- and d-nucleosides, explored the molecular basis of drug resistance which can be utilized for future anti-HBV drug discovery.     

Understanding the molecular basis of HBV drug resistance by molecular modeling

Despite the significant successes in the area of anti-HBV agents, resistance and cross-resistance against available therapeutics are the major hurdles in drug discovery. The present investigation is to understand the molecular basis of drug resistance conferred by the B and C domain mutations of HBV-polymerase on the binding affinity of five anti-HBV agents [lamivudine (3TC, 1), adefovir (ADV, 2), entecavir (ETV, 3), telbivudine (LdT, 4) and clevudine (l-FMAU, 5)]. In this regard, homology modeled structure of HBV-polymerase was used for minimization, conformational search and induced fit docking followed by binding energy calculation on wild-type as well as on mutant HBV-polymerases (L180M, M204V, M204I, L180M + M204V, L180M − M204I). Our studies suggest a significant correlation between the fold resistances and the binding affinity of anti-HBV nucleosides. The binding mode studies reveals that the domain C residue M204 is closely associated with sugar/pseudosugar ring positioning in the active site. The positioning of oxathiolane ring of 3TC (1) is plausible due the induced fit orientation of the M204 residue in wild-type, and further mutation of M204 to V204 or I204 reduces the final binding affinity which leads to the drug resistance. The domain B residue L180 is not directly close (6 Å) to the nucleoside/nucleoside analogs, but indirectly associated with other active-site hydrophobic residues such as A87, F88, P177 and M204. These five hydrophobic residues can directly affect on the incoming nucleoside analogs in terms of its association and interaction that can alter the final binding affinity. There was no sugar ring shifting observed in the case of adefovir (2) and entecavir (3), and the position of sugar ring of 2 and 3 is found similar to the sugar position of natural substrate dATP and dGTP, respectively. The exocyclic double bond of entecavir (3) occupied in the backside hydrophobic pocket (made by residues A87, F88, P177, L180 and M204), which enhances the overall binding affinity. The active site binding of LdT (4) and l-FMAU (5) showed backward shifting along with upward movement without enforcing M204 residue and this significant different binding mode makes these molecules as polymerase inhibitors, without being incorporated into the growing HBV-DNA chain. Structural results conferred by these l- and d-nucleosides, explored the molecular basis of drug resistance which can be utilized for future anti-HBV drug discovery.     

Designing selective COX-2 inhibitors: molecular modeling approaches

Molecular modeling approaches have been successfully used to gain insight into the molecular mechanism of selective cyclooxygenase-2 (COX-2) inhibition. These approaches are based on X-ray structure data and results from structure-activity relationships and site-directed mutagenesis experiments. The recognition process of substrates and inhibitors by COX isoenzymes can be visualized by applying algorithms to describe local properties on the enzyme surface, thus allowing key differences in structure to be studied that may confer differential sensitivity to inhibitors. The virtual screening techniques for COX isoenzymes are rapidly improving, and the search for new selective COX-2 inhibitors has been stimulated by the tremendous success of meloxicam, celecoxib and rofecoxib in the pharmaceutical market and their potential use in new indications.     

Guiding lead optimization with GPCR structure modeling and molecular dynamics

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Supporting the design of efficient dendritic DNA and siRNA nano-carriers with molecular modeling

The design of macromolecules able to generate a stable binding with nucleic acids is of great interest for their possible application in gene delivery. During the last years particular attention has been addressed to the use of dendritic scaffolds as a base to construct efficient DNA and siRNA nano-carriers. Dendrimers and dendrons are hyperbranched polymers characterized by a well-defined structure and by the possibility to functionalize their surface in many different ways. In particular, their multivalent character allows the creation of multiple binding sites between the positively charged groups that decorate the surface of cationic dendrons and dendrimers and the negatively charged phosphate groups present on the strands of DNA and siRNA. The engineering of "ideal dendritic candidates" to deliver and release genetic materials into cells is, however, not trivial due to the huge distance that exists between the design phase and the real application of such molecules. A different architecture of the dendritic scaffold (flexible or rigid) can strongly modify the binding efficiency, but, at the same time, is influenced by the interactions with the external solution. In this context, molecular simulation can represent a "virtual bridge" between the design and the comprehension of the real behavior of such macromolecules.     

Polymorph selection: the role of nucleation, crystal growth and molecular modeling

Solution crystallization is an important separation and purification process used in the chemical, pharmaceutical and food industries. The quality of a crystalline product is generally judged by four main criteria: purity, crystal habit, particle size and solid form. Consistent production of the desired polymorph is crucial as the unanticipated emergence of a different crystal form may have severe consequences. Thus, the selection of a solid-state form for a crystalline product is vital and is ultimately based on knowledge of the properties of the other polymorphs. This review discusses the role of nucleation, crystal growth and molecular modeling on polymorphism in molecular crystals. Examples are presented demonstrating how the first two factors can govern the appearance of a particular crystalline form, and how the latter factor can be used as a tool for understanding polymorphism.     

Chemokines and their receptors: insights from molecular modeling and crystallography

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Evolution of class A G-protein-coupled receptors: implications for molecular modeling

Class A or rhodopsin-like G-protein-coupled receptors (GPCRs) constitute the largest transmembrane receptor family of the human genome. Because of their biological and pharmaceutical importance, the evolutionary history of these receptors has been widely studied. Most studies agree on the classification of the 700 members of this family into a dozen of sub-families. However, the relationship between these sub-families remains controversial and the molecular processes that drove the evolution and diversification of such a large family have still to be determined. We review here the evolutionary analyses carried out on class A GPCRs either by phylogenetic methods or by multidimensional scaling (MDS). We detail the key molecular events driving the evolution of this receptor family. We analyze these events in view of the recently resolved crystal structures of GPCRs and we discuss the usefulness of evolutionary information to help molecular modeling.     

Mathematical modeling of molecular diffusion through mucus

The rate of molecular transport through the mucus gel can be an important determinant of efficacy for therapeutic agents delivered by oral, intranasal, intravaginal/rectal, and intraocular routes. Transport through mucus can be described by mathematical models based on principles of physical chemistry and known characteristics of the mucus gel, its constituents, and of the drug itself. In this paper, we review mathematical models of molecular diffusion in mucus, as well as the techniques commonly used to measure diffusion of solutes in the mucus gel, mucus gel mimics, and mucosal epithelia.     

Grid computing in large pharmaceutical molecular modeling

Most major pharmaceutical companies have employed grid computing to expand their compute resources with the intention of minimizing additional financial expenditure. Historically, one of the issues restricting widespread utilization of the grid resources in molecular modeling is the limited set of suitable applications amenable to coarse-grained parallelization. Recent advances in grid infrastructure technology coupled with advances in application research and redesign will enable fine-grained parallel problems, such as quantum mechanics and molecular dynamics, which were previously inaccessible to the grid environment. This will enable new science as well as increase resource flexibility to load balance and schedule existing workloads.     

用分子模构法建立κ阿片受体激动剂的药效基团

目的：建立非肽类κ阿片受体激动剂的药效基团。方法：从ＭＤＬ ＭＤＤＲ数据库中选出五个高活性非肽类κ阿片受体激动剂，以四氢吡咯环Ｎ原子和乙酰胺基团为叠加点，用分子模构法建立非肽类κ阿片受体激动剂的药效基团。结果：四氢吡咯环、乙酰胺的羰基和与惭酰胺相连的疏水基团为非肽类κ阿片受体激动剂共同结构特征。推测受体Ａｓｐ１３８与甲氢吡咯环的Ｎ原子构成氢键，Ｓｅｒ１８７可能与激动剂的乙酰胺羰基以氢键形式相作用。