Docking-based CoMFA and CoMSIA study of azaindole carboxylic acid derivatives as promising HIV-1 integrase inhibitors

Abstract

Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were performed based on a series of azaindole carboxylic acid derivatives that had previously been reported as promising HIV-1 integrase inhibitors. Docking studies to explore the binding mode were performed based on the highly active molecule 36. The best docked conformation of molecule 36 was used as template for alignment. The comparative molecular field analysis (CoMFA) model (including steric and electrostatic fields) yielded the cross validation q ² = 0.655, non-cross validation r ² = 0.989 and predictive r ² _pred = 0.979. The best comparative molecular similarity indices analysis (CoMSIA) model (including steric, electrostatic, hydrophobic and hydrogen-bond acceptor fields) yielded the cross validation q ² = 0.719, non-cross validation r ² = 0.992 and predictive r ² _pred = 0.953. A series of new azaindole carboxylic acid derivatives were designed and the HIV-1 integrase inhibitory activities of these designed compounds were predicted based on the CoMFA and CoMSIA models.

Keywords:

• 3D-QSAR
• docking
• CoMFA
• CoMSIA
• HIV-1 integrase inhibitors
• azaindole carboxylic acid derivatives

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (grant Nos. 20872082, 21072115 and 21272140).