Identification of dual ligands targeting angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ by core hopping of telmisartan.
It has been reported previously that some angiotensin II receptor blockers not only antagonize angiotensin II type 1 receptor (AT1R), but also exert stimulation in peroxisome proliferator-activated receptor γ (PPARγ) 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 AT1R antagonism and PPARγ 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 AT1R and PPARγ. 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 AT1R (-11.92 kcal/mol) and PPARγ (-13.88 kcal/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 AT1R antagonist and PPARγ partial agonist against hypertension and type 2 diabetes.
a Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy , Tianjin Medical University , Tianjin 300070 , China.
Jun
J
Zhang
a Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy , Tianjin Medical University , Tianjin 300070 , China.
Xin
X
Liu
a Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy , Tianjin Medical University , Tianjin 300070 , China.
Shu-Qing
SQ
Wang
a Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy , Tianjin Medical University , Tianjin 300070 , China.
Gui-You
GY
Liu
b Tianjin Key Laboratory of Molecular Design and Drug Discovery , Tianjin Institute of Pharmaceutical Research , Tianjin 300193 , China.
Wei-Ren
WR
Xu
a Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy , Tianjin Medical University , Tianjin 300070 , China.
Xian-Chao
XC
Cheng
a Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy , Tianjin Medical University , Tianjin 300070 , China.
Run-Ling
RL
Wang
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011487:Protein Conformation; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000378:metabolism; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D008024:Ligands; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D000077333:Telmisartan
ADMET; AT1R; PPARγ; SP docking; molecular dynamics; telmisartan