抑制剂8CA与脂肪细胞脂肪酸结合蛋白(A-FABP)结合模式的分子动力学研究

摘要：脂肪细胞脂肪酸结合蛋白A-FABP(Adipocyte fatty-acid binding protein)是治疗脂质调节生物过程相关疾病的重要靶标. 分子动力学模拟和MM-PBSA方法被采用研究抑制剂8CA与A-FABP结合模式. 研究结果表明静电相互作用和范德华作用驱动了抑制剂8CA与A-FABP的结合。基于残基的能量分解表明抑制剂8CA与R126间的极性相互作用为抑制剂与A-FABP的结合提供了重要贡献. 该残基与8CA的相互作用较好地稳定了抑制剂与A-FABP复合物的稳定性. 我们期望这个研究能为治疗炎症、动脉硬化和代谢病药物设计提供一定的理论指导。     

抑制剂8CA与脂肪细胞脂肪酸结合蛋白(A-FABP)结合模式的分子动力学研究

摘要：脂肪细胞脂肪酸结合蛋白A-FABP(Adipocyte fatty-acid binding protein)是治疗脂质调节生物过程相关疾病的重要靶标. 分子动力学模拟和MM-PBSA方法被采用研究抑制剂8CA与A-FABP结合模式. 研究结果表明静电相互作用和范德华作用驱动了抑制剂8CA与A-FABP的结合。基于残基的能量分解表明抑制剂8CA与R126间的极性相互作用为抑制剂与A-FABP的结合提供了重要贡献. 该残基与8CA的相互作用较好地稳定了抑制剂与A-FABP复合物的稳定性. 我们期望这个研究能为治疗炎症、动脉硬化和代谢病药物设计提供一定的理论指导。     

Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors

对一系列具有抗人乳腺癌细胞系MCF-7生物活性的微管蛋白抑制剂─芳基硫代吲哚衍生物(arylthioindole),进行了三维定量构效关系(3D-QSAR)和对接(docking)研究. 在训练集中,建立了具有良好统计质量和预报能力的比较分子力场分析(CoMFA) 模型,其非交叉验证相关系数平方R₂为0.898,交叉验证相关系数平方q₂为0.654. 同时在测试集的验证中得到预测相关系数平方R₂(pred)为0.816, 进一步表明了该模型具有较高的预测能力. 此外,通过对接研究,获得了这些化合物与微管蛋白作用的键合方式和构象,发现该系列化合物的CoMFA力场分布与对接结合位点上的三维拓朴结构相一致. 根据CoMFA和对接分析的结果,细致地讨论和总结了有利于提高或改进该类化合物活性的主要因素,即在取代基R3、R4和R5上引进高电负性的基团,在取代基R6上引进带有高电负性且大体积的基团,以及在取代基R7上引进小体积的基团等都是有利的. 基于这些研究结果,在理论上还设计了5个新的具有较高活性的化合物.     

Structural insights of dipeptidyl peptidase-IV inhibitors through molecular dynamics-guided receptor-dependent 4D-QSAR studies

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are promising antidiabetic agents. Currently, several DPP-IV inhibitors have been approved for therapeutic use in diabetes mellitus. Receptor-dependent 4D-QSAR is comparatively a new approach which uses molecular dynamics simulations to generate conformational ensemble profiles of compounds representing a dynamic state of compounds at a target’s binding site. This work describes a receptor-dependent 4D-QSAR study on triazolopiperazine derivatives. QSARINS multiple linear regression method was adopted to generate 4D-QSAR models. A model with 9 variables was found to have better predictive accuracy with \({R}^{2}=0.692\), \({Q}^{2}\) (leave-one-out) = 0.592 and \({R}^{2}\) predicted = 0.597. The location of these 9 variables at the binding site of DPP-IV revealed the importance of the residues Val711, Tyr662, Tyr666, Val202, Asp200 and Thr199 in making critical interactions with DPP-IV inhibitors. The study of these critical interactions revealed the structural features required in DPP-IV inhibitors. Thus, in this study the importance of a halogen substituent on a phenyl ring, the extent of substitution on the triazolopiperazine ring, the presence of an ionizable amino group and the presence of a hydrophobic substituent that can bind deeper in binding pocket of DPP-IV were revealed.     

基于分子动力学和自由能计算研究小分子对HIF-VHL相互作用的抑制机理

蛋白-蛋白相互作用涉及多种生理过程. 其中HIF-VHL作为局部缺血性心脏病的重要靶标得到了学术界和工业界的广泛关注. 本文使用分子动力学模拟和结合自由能计算研究pro-like的小分子抑制剂对VHL-HIF的抑制机理. Pro-like抑制剂能够与HIF竞争性地结合在VHL蛋白上,从而破坏VHL-HIF相互作用. 基于抑制机理给出了pro-like抑制剂的优化策略.     

De novo design of N-(pyridin-4-ylmethyl)aniline derivatives as KDR inhibitors: 3D-QSAR, molecular fragment replacement, protein-ligand interaction fingerprint, and ADMET prediction

Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 or kinase insert domain receptor (KDR) have been identified as promising targets for novel anticancer agents. To achieve new potent inhibitors of KDR, we conducted molecular fragment replacement (MFR) studies for the understanding of 3D-QSAR modeling and the docking investigation of arylphthalazines and 2-((1H-Azol-1-yl)methyl)-N-arylbenzamides-based KDR inhibitors. Two favorable 3D-QSAR models (CoMFA with q ², 0.671; r ², 0.969; CoMSIA with q ², 0.608; r ², 0.936) have been developed to predict the biological activity of new compounds. The new molecular database generated by MFR was virtually screened using Glide (docking) and further evaluated with CoMFA prediction, protein?Cligand interaction fingerprint (PLIF) and ADMET analysis. 44 N-(pyridin-4-ylmethyl)aniline derivatives as novel potential KDR inhibitors were finally obtained. In this paper, the work flow developed could be applied to de novo drug design and virtual screening potential KDR inhibitors, and use hit compounds to further optimize and design new potential KDR inhibitors.     

新的相互作用势对MD模拟钙钛矿结构MgSiO3热力学性质的影响

通过分析势能曲线解释了钙钛矿结构MgSiO3熔化模拟过程中模拟熔化温度存在较大差异的原因，并进一步研究了对势参数在分子动力学模拟中的影响. 通过调整已有的经验势得到了一组新的势参数，以此来进行分子动力学研究，得到的常温常压下摩尔体积与Belonoshko和Dubrovinsky的结果符合较好，并且其状态方程、常压下热容和常压下热膨胀系数与他人的实验值都较好地吻合. 另外，所得到的熔化温度也与以前的研究进行了比较.     

In-Silico Study on the Interaction of Saffron Ligands and Beta-Lactoglobulin by Molecular Dynamics and Molecular Docking Approach

Safranal, crocetin, and dimethylcrocetin are secondary metabolites found in saffron and have a wide range of biological activities. An investigation of their interaction with a transport protein, such as β-lactoglobulin (β-lg), at the atomic level could be a valuable factor in controlling their transport to biological sites. The interaction of these ligands and β-lg as a transport protein was investigated using molecular docking and molecular dynamics (MD) simulation methods. The molecular docking results showed that safranal and crocetin bind on the surface of β-lg. However, dimethylcrocetin binds in the internal cavity of β-lg. The β-lg affinity for binding saffron ligands decreases in the following order: crocetin > dimethylcrocetin > safranal. The analysis of MD simulation trajectories showed that the β-lg and β-lg–ligand complexes became stable at approximately 3000 ps and that there was little conformational change in the β-lg–safranal and β-lg–dimethylcrocetin complexes over a 10-ns timescale. In addition, the profiles of atomic fluctuations showed the rigidity of the ligand binding site during the simulation time.     

Insight into binding modes of p53 and inhibitors to MDM2 based on molecular dynamic simulations and principal component analysis

Inhibition of the p53–MDM2 interaction is a new therapeutic strategy to activate the wild-type function of p53 in tumors. Molecular dynamics (MD) simulations and calculations of binding free energies were performed to investigate the binding mechanisms of p53 and two inhibitors PMI and VZV to MDM2. The results show that van der Waals interaction is the main force to control the bindings of ligands to the hydrophobic cleft of MDM2, which basically agrees with the previous calculated and experimental studies. The results from the RMSF calculation, cross-correlation analysis and principal component (PC) analysis prove that the ligand bindings produce a significant effect on the conformation of the binding cleft of MDM2. In addition, the calculations of residue-based free energy decomposition suggest that the CH–CH, CH–π, and π–π interactions dominate the bindings of p53 and inhibitors to MDM2. This study can provide significant help for the design of potent inhibitors targeting the p53–MDM2 interaction.     

Molecular dynamics study of void effect on nanoimprint of single crystal aluminum

Pre-existing defects can alter mechanical behavior of materials significantly under applied load. In current study molecular dynamics (MD) simulations are performed to reveal pre-existing void effect on nanoimprint of single crystal Al thin films, such as deformation mechanism and spring back phenomenon. Current simulation results show void acts as strong barrier to dislocation motion, although plastic deformation is dominantly controlled by dislocation activities. It indicates the void volume fraction has strong influence on nanoimprint: the larger the void volume fraction, the smaller the maximum force required for initial dislocation nucleation, and the stronger the interaction between extended dislocation and void. It also demonstrates that there is a critical void volume fraction for minimum spring back, which is resulted from competition between two roles affecting dislocation annihilation.