Molecular insights into the AT1 antagonism based on biophysical and in silico studies of telmisartan

Abstract

AT<inf>1</inf> antagonists (SARTANs) constitute one of the most successful classes of antihypertensive agents. These molecules interfere with the renin angiotensin system by preventing the vasoconstrictive hormone angiotensin II from binding onto the AT<inf>1</inf> receptor. It is proposed that SARTANs exert their biological action by inserting into the lipid membrane and then diffuse to the active site of AT<inf>1</inf> receptor. In this article, the conformational properties of telmisartan are analyzed both in solution and in the active site of the AT<inf>1</inf> receptor using conformational analysis, molecular docking, Molecular Dynamics (MD) simulations, and in silico Ala-scanning mutagenesis studies. Combined results reveal telmisartan's crucial structural characteristics and classify the importance of receptor's amino acids for ligand binding. Since telmisartan is exerting its activity on a transmembrane receptor, Differential Scanning Calorimetry was applied to study the drug effects in lipid bilayers mimicking the biological membrane environment. Of paramount importance, is the finding that telmisartan exerted similarities but also significant differences with other AT<inf>1</inf> antagonists on the basis of their interaction with lipid bilayers and subsequent docking into the active site. This could in part explain their similar mode of action and in parallel their distinct pharmacological profile. © 2013 Springer Science+Business Media New York. © 2013 Elsevier B.V., All rights reserved.