Drug resistant mechanism of diaryltriazine analog inhibitors of HIV-1 reverse transcriptase using molecular dynamics simulation and 3D-QSAR.
Diaryltriazine inhibitors have highly potent and effective bioactivities for the wild type of HIV-1 reverse transcription. To design new drug of antimutant HIV-1 reverse transcriptase, the mechanism of drug resistance for four types of mutants was revealed. Molecular dynamics simulations suggest that Lys101, Leu100, Lys103, Tyr181, and Tyr188 are key residues. Different mutants of key residues may have different interaction modes and lead to different drug resistances. Then, CoMFA and CoMSIA methods were employed to construct 3D quantitative structure-activity relationship models. These models were evaluated by test set compounds. These models can be used to make quantitative prediction of their bioactivities for lead compounds before resorting to in vitro and in vivo experimentation.
College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai, China.
Zeng
Z
Li
Hao
H
Zhang
Yixue
Y
Li
Jian
J
Zhang
Hai-Feng
HF
Chen
D019943:Amino Acid Substitution / Q000235:genetics; D001665:Binding Sites; D045744:Cell Line, Tumor; D016208:Databases, Factual; D024882:Drug Resistance, Viral / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D056004:Molecular Dynamics Simulation; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology
D018894:Reverse Transcriptase Inhibitors; D014227:Triazines; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase