Li Zeng, Han Jin, Chen Hai-Feng
College of Life Science and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai 200240, China.
Chem Biol Drug Des. 2008 Nov;72(5):350-9. doi: 10.1111/j.1747-0285.2008.00713.x.
HIV-1 reverse transcriptase is a key enzyme playing an important role in the HIV-1 life cycle for the replication of the RNA genome into DNA form. Lys103Asn (K103N) mutant frequently is observed in HIV-1 reverse transcriptase. Therefore, a series of novel non-nucleoside reverse transcriptase inhibitors were designed and synthesized. In vitro experimental results show that diaryltriazine analogs have potent anti-HIV activity with moderate to high selectivity. In order to design anti-HIV drug, docking and molecular dynamics simulation were used to investigate the binding mode between ligand and HIV-1 reverse transcriptase. The results suggest that the analogs might have a similar interaction mechanism with HIV-1 reverse transcriptase. Then comparative molecular field analysis and comparative molecular similarity indices analysis were used to construct quantitative structure-activity models. These models were evaluated by eight test set compounds. These models are helpful in making quantitative prediction of their activity for new lead compounds before resorting in vitro and in vivo experimentation.
HIV-1逆转录酶是一种关键酶，在HIV-1生命周期中，对于将RNA基因组复制为DNA形式起着重要作用。Lys103Asn（K103N）突变体在HIV-1逆转录酶中经常被观察到。因此，设计并合成了一系列新型非核苷逆转录酶抑制剂。体外实验结果表明，二芳基三嗪类似物具有强效抗HIV活性，且具有中等到高度的选择性。为了设计抗HIV药物，采用对接和分子动力学模拟来研究配体与HIV-1逆转录酶之间的结合模式。结果表明，这些类似物可能与HIV-1逆转录酶具有相似的相互作用机制。然后，利用比较分子场分析和比较分子相似性指数分析来构建定量构效关系模型。这些模型通过八个测试集化合物进行评估。这些模型有助于在进行体外和体内实验之前，对新先导化合物的活性进行定量预测。
