Abstract
Carbamazepine (CBZ), a commonly prescribed antiepileptic drug, in human liver, is mainly metabolized by two isoforms of cytochrome P450 (CYP), CYP3A4 and CYP3A5. Therefore, the binding of CBZ with these two enzymes plays crucial role in the biotransformation of the drug into its active metabolite. In the present work, classical molecular dynamics (MD) simulation was used to investigate the detailed interaction mechanism between CBZ and these two CYP isoforms at the atomic level. The results revealed that although CBZ can bind with the two proteins, all kinds of the interactions, including hydrogen bonds, salt bridges, hydrophobic interaction, and π-π interaction, are isoform specific. The specificity directly leads to a binding environment difference at the active sites of the two isoforms, as represented by the electrostatic surface potential maps, which further results in the varied dynamic behavior of CBZ in the two isoforms. Our research will help to deepen the understanding of the physiological functions of CYP isoforms and opens the door for the rational design and development of isoform-specific inhibitors.