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Such inhibition is one of the major causes of drug\u2013drug 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\u2010related predictions. In this work, we employed density functional theory (DFT) and the generalized Kohn\u2013Sham energy decomposition analysis (GKS\u2010EDA) scheme to investigate the nature of the coordination bonding formed in the reversible and quasi\u2010irreversible inhibition of P450s. The GKS\u2010EDA 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\u2010type inhibitors and is particularly prominent for the nitrosoalkane ligand. An additional natural bond orbital (NBO) analysis provided insight into the relative significance of the \u03c3 donation and \u03c0 backdonation effects in various heme\u2013inhibitor complexes.<\/jats:p>","DOI":"10.1002\/asia.202200360","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T00:39:06Z","timestamp":1651797546000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Energy Decomposition Analysis of the Nature of Coordination Bonding at the Heme Iron Center in Cytochrome P450 Inhibition"],"prefix":"10.1002","volume":"17","author":[{"given":"Shuyang","family":"Liu","sequence":"first","affiliation":[{"name":"Warshel Institute for Computational Biology School of Life and Health Sciences The Chinese University of Hong Kong, Shenzhen  Longgang District 518172 Shenzhen P.\u2005R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8239-3471","authenticated-orcid":false,"given":"Hajime","family":"Hirao","sequence":"additional","affiliation":[{"name":"Warshel Institute for Computational Biology School of Life and Health Sciences The Chinese University of Hong Kong, Shenzhen  Longgang District 518172 Shenzhen P.\u2005R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,24]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"\u00a0"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/tx500444e"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.104.000794"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.116.070763"},{"key":"e_1_2_8_5_1","unstructured":"\u00a0"},{"key":"e_1_2_8_6_2","first-page":"391","volume":"76","author":"Lynch T.","year":"2007","journal-title":"Am. Fam. 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