Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARγ

// Jun Zhang 1 , Qing-Qing Hao 1 , Xin Liu 1 , Zhi Jing 1 , Wen-Qing Jia 1 , Shu-Qing Wang 1 , Wei-Ren Xu 2 , Xian-Chao Cheng 1 , Run-Ling Wang 1 1 Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China 2 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China Correspondence to: Xian-Chao Cheng, email: chengxianchao@aliyun.com Run-Ling Wang, email: wangrunling@tmu.edu.cn Keywords: imidazo-\pyridines, AT1, PPARγ, molecular docking, 3D-QSAR Received: December 20, 2016      Accepted: January 27, 2017      Published: February 28, 2017 ABSTRACT Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\pyridine derivatives with the IC 50 s of 0.49~94.1 nM against AT1 and EC 50 s of 20~3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q 2 =0.553, r 2 =0.954, SEE=0.127, r 2 pred =0.779 for AT1 and q 2 =0.503, r 2 =1.00, SEE=0.019, r 2 pred =0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists.