title: Multistage virtual screening and identification of novel HIV-1 protease inhibitors by integrating SVM, shape, pharmacophore and docking methods.
abstract: The HIV-1 protease has proven to be a crucial component of the HIV replication machinery and a reliable target for anti-HIV drug discovery. In this study, we applied an optimized hierarchical multistage virtual screening method targeting HIV-1 protease. The method sequentially applied SVM (Support Vector Machine), shape similarity, pharmacophore modeling and molecular docking. Using a validation set (270 positives, 155,996 negatives), the multistage virtual screening method showed a high hit rate and high enrichment factor of 80.47% and 465.75, respectively. Furthermore, this approach was applied to screen the National Cancer Institute database (NCI), which contains 260,000 molecules. From the final hit list, 6 molecules were selected for further testing in an in vitro HIV-1 protease inhibitory assay, and 2 molecules (NSC111887 and NSC121217) showed inhibitory potency against HIV-1 protease, with IC50 values of 62 μM and 162 μM, respectively. With further chemical development, these 2 molecules could potentially serve as HIV-1 protease inhibitors.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, PR China; College of Pharmacy, Nankai University, Tianjin 300071, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wei
authors.affiliation: College of Pharmacy, Nankai University, Tianjin 300071, PR China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, PR China; College of Life Sciences, Nankai University, Tianjin 300071, PR China.
authors.forename: Zeming
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Oncology, Tianjin Union Medical Center, Tianjin 300180, PR China.
authors.forename: Fengwei
authors.initials: F
authors.lastname: Wang
authors.affiliation: PracticaChem-China, Tianjin 300192, PR China. Electronic address: practicachem@gmail.com.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, PR China; College of Life Sciences, Nankai University, Tianjin 300071, PR China. Electronic address: hongzy@nankai.edu.cn.
authors.forename: Zhangyong
authors.initials: Z
authors.lastname: Hong
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, PR China; College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: jianpinglin@nankai.edu.cn.
authors.forename: Jianping
authors.initials: J
authors.lastname: Lin
mesh_terms: D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D060388:Support Vector Machine
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease
keywords: Docking; HIV-1 protease; Multistage virtual screening; Pharmacophore; SVM; Shape