Selectivity of Valsartan to the Human Angiotensin II Type One Receptors as Assessed by Binding Affinity, Functional Activity and Molecular Modeling

摘要

Investigations were done to establish the precise selectivity of valsartan to the human angiotensin II type 1 receptors. We have first evaluated the binding affinities and functional activities of valsartan to the angiotensin II receptor subtypes and compared these activities with those of other angiotensin II receptor blockers, such as candesartan, losartan, and telmisartan. Molecular modeling studies have been done to acquire more receptor specific ligand-receptor interactions. Site-directed mutagenesis has also been done as predicted by the molecular modeling of valsartan to AT_1 receptor to identify the important binding sites of valsartan to AT_1 receptors and we, therefore, confirmed the precise selectivity of this drag towards AT_1 receptor. We have also showed the inverse agonist activity of valsartan to the constitutively active mutant of AT_1 receptor and receptor internalization in presence of valsartan.