Quionolone carboxylic acid derivatives as HIV‐1 integrase inhibitors: Docking‐based HQSAR and topomer CoMFA analyses

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EarlyView Article

  • Published: Aug 29, 2017
  • Author: Jianbo Tong, Pei Zhan, Xiang Simon Wang, Yingji Wu

Abstract

Quionolone carboxylic acid derivatives as inhibitors of HIV‐1 integrase were investigated as a potential class of drugs for the treatment of acquired immunodeficiency syndrome (AIDS). Hologram quantitative structure‐activity relationships (HQSAR) and translocation comparative molecular field vector analysis (topomer CoMFA) were applied to a series of 48 quionolone carboxylic acid derivatives. The most effective HQSAR model was obtained using atoms and bonds as fragment distinctions: cross‐validation q2 = 0.796, standard error of prediction SDCV = 0.36, the non‐cross‐validated r2 = 0.967, non‐cross validated standard error SD = 0.17, the correlation coefficient of external validation Qext2 = 0.955, and the best hologram length HL = 180. topomer CoMFA models were built based on different fragment cutting models, with the most effective model of q2 = 0.775, SDCV = 0.37, r2 = 0.967, SD = 0.15, Qext2 = 0.915, and F = 163.255. These results show that the models generated form HQSAR and topomer CoMFA were able to effectively predict the inhibitory potency of this class of compounds. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into the HIV‐1 integrase active site, which revealed the likely bioactive conformations. This study showed that there are extensive interactions between the quionolone carboxylic acid derivatives and THR80, VAL82, GLY27, ASP29, and ARG8 residues in the active site of HIV‐1 integrase. These results provide useful insights for the design of potent new inhibitors of HIV‐1 integrase.

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