Energy Decomposition Analysis of the Nature of Coordination Bonding at the Heme Iron Center in Cytochrome P450 Inhibition.
Shuyang LiuHajime HiraoPublished in: Chemistry, an Asian journal (2022)
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 σ donation and π backdonation effects in various heme-inhibitor complexes.