Structures of cytochrome P450 2B4 complexed with the antiplatelet drugs ticlopidine and clopidogrel .

ABSTRACT: Prior X-ray crystal structures of rabbit cytochrome P450 2B4 (2B4) in complexes with various imidazoles have demonstrated markedly different enzyme conformations depending on the size of the inhibitor occupying the active site. In this study, structures of 2B4 were determined with the antiplatelet drugs clopidogrel and ticlopidine, which were expected to have greater freedom of movement in the binding pocket. Ticlopidine could be modeled into the electron density maps in two distinct orientations, both of which are consistent with metabolic data gathered with other mammalian P450 enzymes. Results of ligand docking and heme-induced NMR relaxation of drug protons showed that ticlopidine was preferentially oriented with the chlorophenyl group closest to the heme. Because of its stereocenter,

SUBMITTER: Gay SC 

PROVIDER: S-EPMC3005796 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature