An ab initio study of AT2 antagonists.

In this study we report ab initio molecular orbital calculations on the natural hormone angiotensin II, which induces activity at AT1/AT2 receptor subtypes leading to vasoconstriction and subsequent hypertension, and AT2 antagonists. Pharmacophoric features of AT2 antagonists have been studied. A model of AT2 receptor has been made, and angiotensin II as well as antagonists has been systematically docked and their interactions with the receptor analyzed. Calculated ligand-receptor interaction energies have been correlated with experimentally observed biological potency data. Our studies indicate that antagonists retain sufficient interactions to block the receptor but may not be adequate to induce activity at the receptor. A poor antagonist is, therefore, proposed as a close mimic of angiotensin II in terms of interacting with the receptor. These studies further explore the mechanistic aspects of this important class of drugs.