title: Revealing the drug-resistant mechanism for diarylpyrimidine analogue inhibitors of HIV-1 reverse transcriptase.
abstract: Diaryltriazine (DATA) and diarylpyrimidine (DAPY) were two category inhibitors with highly potent activity for wild type (wt) and four principal mutant types (L100I, K103N, Y181C and Y188L) of HIV-1 reverse transcriptase (RT). We had revealed the drug-resistant mechanism of DATA analogue inhibitors with molecular dynamics simulation and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods. In this work, we investigated the drug-resistant mechanism of DAPY analogue inhibitors. It was found that DAPY analogue inhibitors form more hydrogen bonds and hydrophobic contacts with wild type and mutants of HIV-1 RT than DATA inhibitors. This could explain that DAPY analogue inhibitors are more potent than DATA for the wild type and mutants of HIV-1 RT. Then, 3D-QSAR models were constructed for these inhibitors of wild type and four principal mutant types HIV-1 RT and evaluated by test set compounds. These combined models can be used to design new chemical entities and make quantitative prediction of the bioactivities for HIV-1 RT inhibitors before resorting to in vitro and in vivo experiment.
authors.affiliation: State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, College of Life Science and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Qin
authors.forename: Wei
authors.initials: W
authors.lastname: Ye
authors.forename: Zeng
authors.initials: Z
authors.lastname: Li
authors.forename: Songyao
authors.initials: S
authors.lastname: Ma
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Jiayi
authors.initials: J
authors.lastname: Zhu
authors.forename: Yixue
authors.initials: Y
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Chen
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase