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

Abstract

It has been reported previously that some angiotensin II receptor blockers not only antagonize angiotensin II type 1 receptor (ATR), 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 ATR 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 ATR 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 ATR (-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 ATR antagonist and PPARγ partial agonist against hypertension and type 2 diabetes.

Reliability of Docking-Based Virtual Screening for GPCR Ligands with Homology Modeled Structures: A Case Study of the Angiotensin II Type I Receptor

“…In this study, angiotensin II type 1 receptor (AT1R) was used as the tested case. AT1R is closely related with hypertension and cardiovascular diseases, and AT1R blockade by antagonists can lower blood pressure in hypertensive patients and improves systemic hemodynamics in patients with congestive heart failure. − In 2015, through serial femtosecond crystallography with an X-ray free-electron laser, the crystal structures of AT1R (PDB entries: 4YAY and 4ZUD) in the inactive state in complex with its selective antagonists ZD7155 and olmesartan were determined, and they were then used in docking-based VS. , Before the release of the crystal structures of AT1R, a homology model of AT1R was built based on the crystal structure of bovine rhodopsin and used in molecular docking, but the quality of this model was not evaluated . A well-known rule of thumb for homology modeling is that once the target-template sequence identity is below 30%, the quality of the resulting homology model may not be guaranteed.…”

Computation-Directed Molecular Design, Synthesis, and Fungicidal Activity of Succinate Dehydrogenase Inhibitors

“…Finally, collecting and analyzing the root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and the protein−ligand interaction and hydrogen bond interaction at the simulation were performed to reflect the correlation of the protein− ligand complex. 28 Binding Free Energy Calculations. In this study, the MM-GBSA of Prime module of Maestro 12.8 software was used to calculate the binding free energy.…”

Design, Synthesis, Molecular Docking Analysis and Biological Evaluations of 4-[(Quinolin-4-yl)amino]benzamide Derivatives as Novel Anti-Influenza Virus Agents

“…The temperature was set to 300 K and the pressure was set to 1.01325 bar. Finally, the 100 ns MD simulations were carried out (record the time interval of each trajectory at every 100 PS) [ 60 , 61 , 62 ].…”