The human cytochrome P450 enzymes (CYPs) carry out oxidations of a broad spectrum of substrates. Consequently, they play a critical role in the metabolism of xenobiotics such as drugs and carcinogens. Bioavailability and toxicity, both of which can be related to CYPs, continue to pose problems in the development of new drugs. The isoform that metabolizes over one third of drugs, CYP 3A4, was investigated employing ensemble-docking experiments of substrate and inhibitor libraries with Induced Fit Docking and a number of scoring functions. Enzyme conformations included three currently available crystal 3A4 structures. All docking experiments were performed in duplicates with and without inclusion of crystallographic waters. Resultant poses were assessed based on accuracy of site of metabolism prediction, and/or feasibility of the drug-3A4 generated complexes. Our analyses suggest that certain residues make favorable interactions with bound ligands. Employing multiple receptor conformations enhances the accuracy of catalytic prediction, while ligand size and flexibility impact docking performance. The presence of waters observed in crystal complexes does not necessarily lead to improved performance.

Exploring flexibility and molecular recognition in the human cytochrome 3A4

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.