State Key Laboratory of Microbial metabolism, Department of Bioinformatics and Biostatistics, College of Life Sciences and Biotechnology, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai 200240, China.
Chem Biol Drug Des. 2012 Jun;79(6):916-25. doi: 10.1111/j.1747-0285.2012.01348.x. Epub 2012 Feb 20.
HIV protease is a key enzyme to play a key role in the HIV-1 replication cycle and control the maturation from HIV viruses to an infectious virion. HIV-1 protease has become an important target for anti-HIV-1 drug development. Here, we used molecular dynamics simulation to study the binding mode between mannitol derivatives and HIV-1 protease. The results suggest that the most active compound (M35) has more stable hydrogen bonds and stable native contacts than the less active one (M17). These mannitol derivatives might have similar interaction mode with HIV-1 protease. Then, 3D-QSAR was used to construct quantitative structure-activity models. The cross-validated q(2) values are found as 0.728 and 0.611 for CoMFA and CoMSIA, respectively. And the non-cross-validated r(2) values are 0.973 and 0.950. Nine test set compounds validate the model. The results show that this model possesses better prediction ability than the previous work. This model can be used to design new chemical entities and make quantitative prediction of the bioactivities for HIV-1 protease inhibitors before resorting to in vitro and in vivo experiment.
HIV 蛋白酶是 HIV-1 复制周期中发挥关键作用的关键酶，控制 HIV 病毒向感染性病毒颗粒的成熟。HIV-1 蛋白酶已成为抗 HIV-1 药物开发的重要靶点。在这里，我们使用分子动力学模拟研究甘露醇衍生物与 HIV-1 蛋白酶的结合模式。结果表明，最活跃的化合物（M35）比不活跃的化合物（M17）具有更稳定的氢键和稳定的天然接触。这些甘露醇衍生物可能与 HIV-1 蛋白酶具有相似的相互作用模式。然后，我们使用 3D-QSAR 构建定量构效关系模型。CoMFA 和 CoMSIA 的交叉验证 q(2) 值分别为 0.728 和 0.611。非交叉验证 r(2) 值分别为 0.973 和 0.950。9 个测试集化合物验证了该模型。结果表明，该模型比以前的工作具有更好的预测能力。该模型可用于设计新的化学实体，并在进行体外和体内实验之前对 HIV-1 蛋白酶抑制剂的生物活性进行定量预测。
