Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, India.
SAR QSAR Environ Res. 2013;24(9):753-71. doi: 10.1080/1062936X.2013.792870. Epub 2013 May 28.
Hydroxamic acid derivatives with metal ion binding properties were collected from the literature to generate a pharmacophore and 3D-QSAR model for HIV strand transfer inhibition. The derived pharmacophore model (AAAHRR) recognizes both metal ion binding site and hydrophobic group. The QSAR model generated using this hypothesis expressed statistical significance (r(2) = 0.971 for the training set and q(2) = 0.913 for the test set). The ability of this pharmacophore model to retrieve other metal ion binding inhibitors was examined by screening the ChemBank database (ligandinfo) incorporated with 10 known strand transfer inhibitors. The studied favourable and unfavourable contours of chemical features (H-bond donor, acceptor and hydrophobic sites) revealed the role of hydrophobic substitution at the fluorobenzene ring and cyclization of the metal ion binding hydroxamic acid in effective integrase inhibition. Analysis of the frontier orbitals, HOMO and LUMO revealed that the nucleophilic / electrophilic interactions depend on the significant overlapping observed at the azaindole and hydroxamic acid groups. In essence, the generated pharmacophore model is competent enough to disclose the essential site-specific interactions involved in the inhibition of HIV integrase, and hence can be used in virtual screening to identify novel scaffolds as leads with increased anti-viral potency.
收集了具有金属离子结合特性的羟肟酸衍生物，用于生成 HIV 链转移抑制的药效团和 3D-QSAR 模型。推导的药效团模型（AAAHRR）识别金属离子结合位点和疏水区。使用该假设生成的 QSAR 模型在统计学上具有显著意义（训练集的 r(2) = 0.971，测试集的 q(2) = 0.913）。通过筛选包含 10 种已知链转移抑制剂的 ChemBank 数据库（ligandinfo），检查了该药效团模型检索其他金属离子结合抑制剂的能力。研究了有利和不利的化学特征（氢键供体、受体和疏水部位）轮廓，揭示了氟苯环上的疏水性取代和金属离子结合羟肟酸的环化在有效整合酶抑制中的作用。前线轨道、HOMO 和 LUMO 的分析表明，亲核/亲电相互作用取决于在氮茚和羟肟酸基团中观察到的显著重叠。从本质上讲，生成的药效团模型足以揭示 HIV 整合酶抑制中涉及的关键特定相互作用，因此可用于虚拟筛选，以确定具有更高抗病毒活性的新型支架作为先导物。
