Razzaghi-Asl Nima, Sepehri Saghi, Ebadi Ahmad, Miri Ramin, Shahabipour Sara
Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran. ; Drug and Advanced Sciences Research Center, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran.
Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences.
Iran J Pharm Res. 2015 Summer;14(3):785-802.
Human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) is a disease pertained to the human immune system. Given its crucial role in viral replication, HIV-1 protease (HIV-1 PR) is a prime therapeutic target in AIDS therapy. In this regard, the dynamic aspects of ligand-enzyme interactions may indicate an important role of conformational variability in HIV-1 PR inhibitor/drug design. In the present contribution, the effect of HIV-1 PR flexibility (within multiple crystallographic structures of HIV-1 PR) on binding to the Amprenavir was elucidated via an ensemble docking approach. Molecular docking studies were performed via advanced AutoDock4.2 software. Ensemble docking of Amprenavir into the active site of various conformations of HIV-1 PR predicted different interaction modes/energies. Analysis of binding factors in terms of docking false negatives/positives revealed a determinant role of enzyme conformational variation in prediction of optimum induced fit (PDB ID: 1HPV). The outcomes of this study demonstrated that conformation of receptor may significantly affect the accuracy of docking/binding results in structure-based rational design of anti HIV-1 PR agents. Furthermore; some strategies to re-score the docking results in HIV-1 PR targeted docking studies were proposed.
人类免疫缺陷病毒感染/获得性免疫缺陷综合征（HIV/AIDS）是一种与人体免疫系统相关的疾病。鉴于HIV-1蛋白酶（HIV-1 PR）在病毒复制中起关键作用，它是艾滋病治疗中的主要治疗靶点。在这方面，配体-酶相互作用的动态方面可能表明构象变异性在HIV-1 PR抑制剂/药物设计中具有重要作用。在本研究中，通过整体对接方法阐明了HIV-1 PR的灵活性（在HIV-1 PR的多个晶体结构内）对与安普那韦结合的影响。分子对接研究通过先进的AutoDock4.2软件进行。将安普那韦整体对接至HIV-1 PR的各种构象的活性位点，预测出不同的相互作用模式/能量。根据对接假阴性/阳性分析结合因子，揭示了酶构象变化在预测最佳诱导契合（PDB ID：1HPV）中的决定性作用。本研究结果表明，在基于结构的抗HIV-1 PR药物合理设计中，受体构象可能会显著影响对接/结合结果的准确性。此外，还提出了一些在针对HIV-1 PR的对接研究中重新评估对接结果的策略。
