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Crystal structures of the human angiotensin II type 1 receptor (AT 1 R) complex with the antihypertensive agent ZD7155 (PDB id: 4YAY ) and the blood pressure medication Benicar (PDB id: 4ZUD ) showed that binding poses of both antagonists are similar. This finding implies that clinically used angiotensin receptor blocking (ARB) drugs may interact in a similar fashion. However, clinically observed differences in pharmacological and therapeutic efficacies of ARBs lead to the question of whether the dynamic interactions of AT 1 R with ARBs vary. To address this, we performed induced-fit docking (IFD) of eight clinically used ARBs to AT 1 R followed by 200 ns molecular dynamic (MD) simulation. The experimental K i values for ARBs correlated remarkably well with calculated free energy with R 2 = 0.95 and 0.70 for AT 1 R-ARB models generated respectively by IFD and MD simulation. The eight ARB-AT 1 R complexes share a common set of binding residues. In addition, MD simulation results validated by mutagenesis data discovered distinctive spatiotemporal interactions that display unique bonding between an individual ARB and AT 1 R. These findings provide a reasonably broader picture reconciling the structure-based observations with clinical studies reporting efficacy variations for ARBs. The unique differences unraveled for ARBs in this study will be useful for structure-based design of the next generation of more potent and selective ARBs.

Divergent Spatiotemporal Interaction of Angiotensin Receptor Blocking Drugs with Angiotensin Type 1 Receptor