3D-QSAR Modeling, Surflex Docking and Reverse Docking Studies of Diketo-Acid Derivatives as Potent Integrase/Rnase H Inhibitors

作者：Chang, Zichao; Wang, Rui; Ding, Xuelei; An, Chunhong; Hu, Yong; Wang, Yuanqiang; Shu, Mao^*; Lin, Zhihua^*

来源：Latin American Journal of Pharmacy, 2016, 35(5): 895-904.

• Integrase/RNase H Inhibitors
• 3D-QSAR
• Surflex-dock
• Reverse docking

HIV-1 Integrase and Ribonuclease H (Rnsae H) dual inhibitors can improve therapeutic efficiency of AIDS, which combine two different desired pharmacological actions at a similar effective dose. Furthermore, this innovative approach can overcome drug-drug interactions of highly active antiretroviral therapy (HAART). In order to design and optimize the potent dual Integrase/Rnase H Inhibitors, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used to analysis 3D structure-activity relationships (3D-QSAR). For Integrase inhibitors, the 3D-QSAR model (CoMFA with q(2), 0.656; r(2), 0.971; CoMSIA with q(2), 0.559; r(2), 0.944) had a good predictability, and for RNase H inhibitors, the 3D-QSAR model (CoMFA with q(2), 0.645; r(2), 0.997; CoMSIA with q(2), 0.651; r(2), 0.946) also had good predictability. The surflex-dock was used to reveal the binding mode between inhibitors and receptors. We also took advantage of reverse-dock exploring the underlying toxicity of dual inhibitors. Finally, combining 3D contour maps with surflex-dock results, fifteen derivatives as potential dual inhibitors were designed to further test established 3D-QSAR models. Among them, compound 65 could become the clinical leading compound theoretically.

• 出版日期2016
• 单位重庆理工大学; 重庆大学