Molecular mechanism of action for reversible P2Y12 antagonists

Recently, reversible antagonists of the P2Y(12) receptor have been reported. However, the mechanisms of binding have not been elucidated. To this end, a number of homology models were built by means of three programs from four templates. A consensus model was derived from those initial models. The final model was created by refining the consensus model with molecular dynamics simulations. The agonist and antagonists of P2Y(12) have been docked in the final model. For the agonist, the Arg256, Lys280, and Phe252 are "hot" residues. For the antagonists, the Lys280 and Phe252 are "hot" residues that have hydrogen bonding contacts and pi-pi interactions, respectively. These results can explain the observations of mutation experiments and can guide the design of new inhibitors. (C) 2011 Elsevier B.V. All rights reserved.