Brigo A, Mustata G Iurcu, Briggs J M, Moro S
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Padova, 35131 Padova, Italy.
Med Chem. 2005 May;1(3):263-75. doi: 10.2174/1573406053765440.
Over the past 10 years, classical computer-aided molecular design methods have not been frequently applied for the discovery of novel HIV-1 integrase (IN) inhibitors, due to the intrinsic challenges that this enzyme presents. Therefore, a novel approach that combines the chemical information of known integrase inhibitors with the enzyme's detailed 3D structure in a stepwise fashion is proposed: (I) use of a pharmacophore model (PM), which takes into account in a weighted fashion the chemical features of known ligands, in analogous manner to the to search the Maybridge and the NCI 3D databases; (II) drug-likeness optimization; (III) virtual high-throughput screening of the hits matching the PM query against 1QS4 wild-type IN structure using different Docking/Scoring combinations; (IV) visual inspection and selection of the hits in function of: binding free energies; binding mode type within the active site; retrieval among the best 20% hits in more than 6 Docking/Scoring protocols at the same time. This approach aims at a rational selection of new potential HIV-1 integrase inhibitors.
在过去十年中，由于HIV-1整合酶（IN）存在内在挑战，经典的计算机辅助分子设计方法并未频繁用于发现新型HIV-1整合酶抑制剂。因此，本文提出了一种新颖的方法，该方法将已知整合酶抑制剂的化学信息与酶的详细三维结构逐步结合起来：（I）使用药效团模型（PM），该模型以加权方式考虑已知配体的化学特征，类似于搜索Maybridge和NCI 3D数据库的方式；（II）类药性质优化；（III）使用不同的对接/评分组合，对与PM查询匹配的命中物针对1QS4野生型IN结构进行虚拟高通量筛选；（IV）根据以下功能对命中物进行目视检查和选择：结合自由能；活性位点内的结合模式类型；在超过6种对接/评分方案中同时在最佳20%命中物中检索。该方法旨在合理选择新的潜在HIV-1整合酶抑制剂。
