Dhaked Devendra K, Verma Jitender, Saran Anil, Coutinho Evans C
Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, 400 098, India.
J Mol Model. 2009 Mar;15(3):233-45. doi: 10.1007/s00894-008-0399-4. Epub 2008 Dec 2.
Since the recognition of HIV-1 integrase as a novel and rational target for HIV therapeutics, remarkable progress has been made in the development of integrase inhibitors. Computational techniques have played a critical role in accelerating research in this area. However, most previous computational studies were based solely on ligand information. In the present work, we describe the application of one of our recently developed receptor-based 3D-quantitative structure activity relationships (QSAR) methods, i.e. comparative residue interaction analysis (CoRIA), in exploring the events involved in ligand-integrase binding. In this methodology, the non-bonded interaction energies (van der Waals and Coulombic) of the inhibitors with individual active site residues of the integrase enzyme are calculated and, along with other thermodynamic descriptors, are correlated with biological activity using chemometric methods. Different combinations of descriptors were used to develop three types of QSAR models, all of which were found to be statistically significant by internal and external validation. This is the first report of such a dedicated receptor-based 3D-QSAR approach being applied to comprehend the integrase-inhibitor recognition process. In addition, the study was performed on 13-different series of inhibitors, thereby exploring the most structurally diverse data set ever used in understanding the inhibition of HIV-1 integrase. The major advantage of this technique is that it can quantitatively extract crucial residues and identify the nature of interactions between the ligand and receptor that modulate activity. The models suggest that Asp64, Thr66, Val77, Asp116, Glu152 and Lys159 are the key residues influencing the binding of ligands with the integrase enzyme, and the majority of these results are in line with earlier studies. The approach facilitates easy lead-to-hit conversion and design of novel inhibitors by optimisation of the interaction of ligands with these specific residues of the integrase enzyme.
自从认识到HIV-1整合酶是一种新型且合理的HIV治疗靶点以来，整合酶抑制剂的开发取得了显著进展。计算技术在加速该领域的研究中发挥了关键作用。然而，以前的大多数计算研究仅基于配体信息。在本工作中，我们描述了我们最近开发的一种基于受体的三维定量构效关系（3D-QSAR）方法，即比较残基相互作用分析（CoRIA），在探索配体与整合酶结合所涉及的事件中的应用。在这种方法中，计算抑制剂与整合酶单个活性位点残基的非键相互作用能（范德华力和库仑力），并与其他热力学描述符一起，使用化学计量学方法与生物活性相关联。使用不同的描述符组合开发了三种类型的QSAR模型，通过内部和外部验证发现所有这些模型都具有统计学意义。这是首次报道这种专门的基于受体的3D-QSAR方法被应用于理解整合酶-抑制剂识别过程。此外，该研究对13个不同系列的抑制剂进行，从而探索了在理解HIV-1整合酶抑制作用中使用的结构最多样化的数据集。该技术的主要优点是它可以定量提取关键残基，并确定调节活性的配体与受体之间相互作用的性质。模型表明，Asp64、Thr66、Val77、Asp116、Glu152和Lys159是影响配体与整合酶结合的关键残基，这些结果中的大多数与早期研究一致。该方法通过优化配体与整合酶这些特定残基的相互作用，便于轻松地将先导物转化为命中物并设计新型抑制剂。
