Molecular Docking of 3-Methylindole-containing Drugs Binding into CYP3A4

Drugs SPD-304(6,7-dimethyl-3-{[methyl-(2-{methyl-[1-(3-trifluoromethyl-phenyl)-1H-indol-3-ylmethyl]- amino}-ethyl)-amino]-methyl}-chromen-4-one) and zafirlukast contain a common structural element of 3-substituted indole moiety which closely relates to a dehydrogenated reaction catalyzed by cytochrome P450s(CYPs). It was reported that the dehydrogenation can produce a reactive electrophilic intermediate which cause toxicities and inactivate CYPs. Drug L-745,870(3-{[4-(4-chlorophenyl)piperazin-1-yl]-methyl}-1H-pyrrolo- 2,3-β-pyridine) might have similar effect since it contains the same structural element. We used molecular docking approach combined with molecular dynamics(MD) simulation to model three-dimensional(3D) complex structures of SPD-304, zafirlukast and L-745,870 into CYP3A4, respectively. The results show that these three drugs can stably bind into the active site and the 3-methylene carbons of the drugs keep a reasonable reactive distance from the heme iron. The complex structure of SPD-304-CYP3A4 is in agreement with experimental data. For zafirlukast, the calculation results indicate that 3-methylene carbon might be the dehydrogenation reaction site. Docking model of L-745,870-CYP3A4 shows a potential possibility of L-745,870 dehydrogenated by CYP3A4 at 3-methylene carbon which is in agreement with experiment in vivo. In addition, residues in the phenylalanine cluster as well as S119 and R212 play a critical role in the ligands binding based on our calculations. The docking models could provide some clues to understand the metabolic mechanism of the drugs by CYP3A4.     

超临界水的分子动力学模拟

采用分子动力学(MD)模拟的方法对超临界条件下水的结构及扩散性质进行了研究.模拟结果表明超临界条件下水分子之间的氢键作用明显减弱,分子极性大大降低.扩散性质与常温下相比,其大小约上升了两个数量级.     

Evaluation of the effect of the chiral centers of Taxol on binding to β-tubulin: A docking and molecular dynamics simulation study

Taxol is one of the most important anti-cancer drugs. The interaction between different variants of Taxol, by altering one of its chiral centers at a time, with β-tubulin protein has been investigated. To achieve such goal, docking and molecular dynamics (MD) simulation studies have been performed. In docking studies, the preferred conformers have been selected to further study by MD method based on the binding energies reported by the AutoDock program. The best result of docking study which shows the highest affinity between ligand and protein has been used as the starting point of the MD simulations. All of the complexes have shown acceptable stability during the simulation process, based on the RMSDs of the backbone of the protein structure. Finally, MM-GBSA calculations have been carried out to select the best ligand, considering the binding energy criteria. The results predict that two of the structures have better affinity toward the mentioned protein, in comparison with Taxol. Three of the structures have affinity similar to that of the Taxol toward the β-tubulin.     

Computational efforts to identify natural occurring compounds from phyllanthus niruri that target hepatitis B viral infections: DFT,docking and dynamics simulation study

Hepatitis B virus (HBV) is an enveloped hepatotropic virus responsible for nucleic acids replication. It causes chronic infection. Depending on the strain, mutations in the core protein of chronic hepatitis B virus (HBV) infections occur. Medicinal plants, the backbone of traditional medicine, are a potential source of lead molecules in drug discovery due to extensive pharmacological studies. In this study, we have screened twenty-nine phytochemicals. The ADME and drug-likeness of these phytochemicals were investigated. After screening, the binding affinity of ten phytochemicals was studied through molecular docking. Simulation studies were carried out for 100 ns to analyze the properties of RMSD, Rg, RMSF, average hydrogen bond number and SASA of hepatitis B virus capsid protein. As per the docking results phyllanthosterol, may be used as a potential inhibitors against HBV. The simulations findings revealed that, in case of mutant protein, the flexibility nature decreases as compared to wildtype protein. Our results may provide useful information for drug design and to lead the identification of novel inhibitor for hepatotropic viral infection.     

甲状腺结合前清蛋白的理论研究

甲状腺结合前清蛋白TTR是一种具有重要生理功能的蛋白质,它是约30种与淀粉样疾病相关的非同源蛋白中的一种。与TTR相关的淀粉样疾病主要有：家族淀粉化心肌疾病,家族淀粉化神经系统疾病,老年系统性淀粉样病变,以及中枢神经系统选择性淀粉化疾病等。这些疾病是由TTR四聚体解聚过程中错误折叠形成cross-β-sheet结构形态的淀粉样纤维所导致。本文介绍了TTR的生理功能及结构特征,并综述了到目前为止用分子动力学模拟、分子对接和定量构效关系等方法在研究TTR淀粉样机理及TTR和小分子相互作用过程中的计算化学研究成果,为基于TTR结构的TTR淀粉样抑制剂药物分子的设计和筛选提供有力参考。     

全氟丙酸与人血清白蛋白结合作用机制的计算模拟与光谱法研究

通过分子对接和动力学模拟的计算方法模拟人血清白蛋白（HSA）的三维空间结构,建立了HSA与全氟丙酸(IPC-PFFA-3)相互作用的模型,研究了HSA与全氟丙酸复合物在水溶液中的稳定性以及在结合位点中的动力学性质。在模拟人体生理的实验条件下,采用荧光光谱法和同步荧光光谱法研究了HSA与IPC-PFFA-3的相互作用。实验结果表明,IPC-PFFA-3与HSA形成的复合物HSA-IPC-PFFA-3对HSA产生荧光猝灭作用,其猝灭机理是静态猝灭;热力学参数计算得出两者结合的主要作用力为氢键作用力;竞争实验的结果表明IPC-PFFA-3与HSA的结合位点位于HSA的SiteⅡ,与分子对接的模拟结果相吻合。同步荧光光谱实验与动力学模拟的结果证明IPC-PFFA-3与HSA能够稳定结合,并使HSA的构象发生变化。     

New salen-type manganese(III) Schiff base complexes derived from meso-1,2-diphenyl-1,2-ethylenediamine: In vitro anticancer activity,mechanism of action,and molecular docking studies

Four new manganese(III) Schiff base complexes (1–4) were synthesized and characterized. The complexes have general formula [MnClL^x] in which L represents a Schiff base ligand derived from condensation of meso-1,2-diphenyl-1,2-ethylenediamine with salicylaldehyde or its 3-OMe-, 5-Br-, or 5-OMe-derivatives (x = 1–4, respectively). The crystal structure of [MnClL¹] (1) was characterized by X-ray crystallography. The in vitro anticancer activity of these complexes was evaluated by MTT and apoptosis assays against human breast (MCF-7) and liver (Hep G2) cancer cells. The complexes exhibited considerable antiproliferative activity against both cell lines (IC₅₀ = 10.8–21.02 μM) comparable to cis-platin, except 4 (MCF-7). The highest activity was found for 1 with IC₅₀ values of 13.62 μM (MCF-7) and 10.8 μM (Hep G2). Flow cytometry experiments showed that 1 induced apoptosis on MCF-7 tumor cell line. Docking simulations using AUTODOCK were also carried out. The results showed that all complexes fitted into the minor groove region of DNA.     

Discovery of a novel serine protease inhibitor utilizing a structure-based and experimental selection of fragments technique

We report a set of strategies to develop novel ligands (Structure Based and Experimental Selection of Fragments: SbE-SF). First, a docking simulation utilizing DOCK3.5 is performed in order to screen the fragment database, which was generated with the in-house program FRAGMENT++ specifically for docking simulation purposes. Although the affinity of these small molecules (fragments) is expected to be low, the affinity of fragments selected by computation is assayed by experiment to determine which ones can be potent inhibitors. After determining such key fragments, additional fragments are attached to the key ones in order to increase the binding affinity,taking into account the binding modes predicted by computation. This method has been applied to a thrombin inhibitor study, resulting in the discovery of a novel inhibitor exhibiting pIC₅₀ = 7.9.