结合分子相似性、药效团和分子对接筛选新的HIV-1蛋白酶抑制剂

Discovery of new HIV-1 protease inhibitors by integrating molecular similarity,pharmacophore and docking methods

结合分子相似性、药效团和分子对接建立兼顾计算效率和预测准确度的HIV-1蛋白酶抑制剂筛选方法。首先通过对现有HIV-1蛋白酶抑制剂分子进行相似性分析,选取代表性的HIV-1蛋白酶抑制剂作为模板分子,构建和优化药效团模型,并从1万个化合物中优先筛选出500个化合物。而后采用分子对接方法进一步考察化合物与HIV-1蛋白酶结合情况,得到4个新的活性候选化合物,并进行其结合自由能计算和抗突变性分析。结果表明新候选化合物ST025723和HIV-1蛋白酶表现出较好的相互作用和抗突变性,具有深入研究的价值,同时也证明分子相似性、药效团和分子对接相结合能够快速有效地发现新颖活性候选化合物。

An efficient and accurate method was established for HIV-1 protease inhibitor screening by integrating molecular similarity,pharmacophore and docking methods. First,the similarity of known HIV-1 protease inhibitors was analyzed,and representative inhibitors were chosen as templates to build pharmacophore model for database screening. Five hundred compounds were picked out from 10 000 compounds by pharmacophore screening,which were further submitted to docking experiment. Four new candidate compounds were obtained,and their binding free energies and antimutagenic abilities were further evaluated. The candidate compound ST025723 showed good interactions with HIV-1 protease and antimutagenic ability,and deserved to be further studied. Therefore,the combination of molecular similarity,pharmacophore,and docking could be an efficient strategy to discover novel active candidates.