基于结构的HIV-1蛋白酶抑制剂的虚拟筛选

Discovery of Protease Inhibitors of HIV- 1 through Structure Based Virtual Screening

目的通过新的虚拟筛选工具PyRx运行AutoDock Vina,对ZINC数据库的2万个化合物进行虚拟筛选,发现新的HIV蛋白酶抑制剂,并且对新的抑制剂与HIV蛋白酶的结合模型进行探索.方法以HIV蛋白酶为靶点,通过虚拟筛选程序AutoDock Vina对ZINC数据库的化合物进行虚拟筛选.与以前研究不同的是,本研究通过新的虚拟筛选工具PyRx运行AutoDock Vina.HIV蛋白酶晶体结构(PDB ID:4phv)从PDB下载,通过AutoDockTools对结构进行处理.化合物结构下载自ZINC数据库,通过PyRx导入,处理成pdbqt格式.PyRx运行AutoDock Vina以后,筛选以后的化合物构象导入AutoDockTools进行分析,数据处理用PyMOL完成.结果从大约2万个化合物库中进行高通量筛选,得到1 000个类药小分子化合物的库.再从这1 000个小分子化合物中筛选针对蛋白酶的抑制剂.通过对建立的化合物数据库进行3轮筛选,发现5个高活性的HIV蛋白酶抑制剂.结论 5个新的抑制剂的进一步开发,将对HIV的治疗和基础研究带来帮助.也对药物虚拟筛选和基于结构的药物开发提供新的信息.

Objective Through new virtual screening tools of PyRx to run AutoDock Vina to virtually screen the 20000 compounds in ZINC database, so as to discover new HIV protease inhibitors, and make a tentative study of the combination model of them with HIV protease. Methods The study focused on the targets of HIV protease, the virtual screening program of AntoDock Vina was used to virtually screen the compounds in ZINC database. It was differing from previous studies by using new virtual screening tools of PyRx to run AutoDock Vina. The HIV protease crystal structure （PDB ID： 4phv） was downloaded from PDB and dealed with AutoDock Tools. Compound structure was downloaded from ZINC database and imported with PyRx, processed into format of pdbqt. The post-screen compounds were imported into AutoDockTools, and the data were outputted with PyMOL. Results There were 1000 drugs of small molecular compound for high-throughput screening from about 20000 compounds in the library. After screening for 3 times we found five highly active HIV protease inhibitors from the 1000 small molecular compounds. Conclusion The further development of the five new HIV protease inhibitors will contribute to the treatment and basic research of HIV, and provide new reference for structure-based virtual screening and discovery of HIV drugs.