Energy Decomposition Analysis of the Nature of Coordination Bonding at the Heme Iron Center in Cytochrome P450 Inhibition

Drug compounds or their metabolic intermediates (MIs) sometimes inhibit the function of cytochrome P450 enzymes (P450s) by forming a coordination bond with the Fe(III) heme or Fe(II) heme of P450s. Such inhibition is one of the major causes of drug-drug interactions (DDIs), a subject of longstanding academic and practical interest. However, such coordination bonding is not fully understood at the quantum mechanical level, thus hampering rational improvement of the accuracy of DDI-related predictions. In this work, we employed density functional theory (DFT) and the generalized Kohn-Sham energy decomposition analysis (GKS-EDA) scheme to investigate the nature of the coordination bonding formed in the reversible and quasi-irreversible inhibition of P450s. The GKS-EDA results highlighted a previously unrecognized role of the electron correlation effect in P450 inhibition. The correlation effect tends to be larger in Fe(II) complexes of MI-type inhibitors and is particularly prominent for the nitrosoalkane ligand. An additional natural bond orbital (NBO) analysis provided insight into the relative significance of the sigma donation and pi backdonation effects in various heme-inhibitor complexes.