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- Title
Revealing the Drug-Resistant Mechanism for Diarylpyrimidine Analogue Inhibitors of HIV-1 Reverse Transcriptase.
- Authors
Hao Zhang; Fang Qin; Wei Ye; Zeng Li; Songyao Ma; Yan Xia; Yi Jiang; Jiayi Zhu; Yixue Li; Jian Zhang; Hai-Feng Chen
- 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.
- Subjects
DRUG resistance; HIV; REVERSE transcriptase inhibitors; DNA polymerases; MOLECULAR dynamics
- Publication
Chemical Biology & Drug Design, 2011, Vol 78, Issue 3, p427
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/j.1747-0285.2011.01163.x