Identification of dual ligands targeting angiotensin II type 1 receptor and peroxisome proliferator-activated receptor- by core hopping of telmisartan

摘要

It has been reported previously that some angiotensin II receptor blockers not only antagonize angiotensin II type 1 receptor (AT(1)R), but also exert stimulation in peroxisome proliferator-activated receptor (PPAR) partial activation, among which telmisartan displays the best. Telmisartan has been tested as a bifunctional ligand with antihypertensive and hypoglycemic activity. Aiming at more potent leads with selective AT(1)R antagonism and PPAR partial agonism, the three parts of telmisartan including the distal benzimidazole ring, the biphenyl moiety, and the carboxylic acid group experienced modification by core hopping method in our study. The central benzimidazole ring, however, remained intact considering its great affinity toward AT(1)R and PPAR. We utilized computational techniques for the sake of details on the binding interactions and conformational stability. Standard precision docking analysis and absorption, distribution, metabolism, excretion, and toxicity prediction received 10 molecules with higher Glide scores, similar interactions, and improved pharmacokinetic profiles compared to telmisartan. Comp#91 with highest scores for AT(1)R (-11.92kcal/mol) and PPAR (-13.88kcal/mol) exhibited excellent binding modes and pharmacokinetic parameters. Molecular dynamics trajectories on best docking pose of comp#91 confirmed the docking results and verified the conformational stability with both receptors throughout the course of 20-ns simulations. Thus, comp#91 could be identified as a promising lead in the development of dual AT(1)R antagonist and PPAR partial agonist against hypertension and type 2 diabetes.