{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T09:54:12Z","timestamp":1787997252908,"version":"build-2784847793"},"reference-count":32,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,22]],"date-time":"2023-01-22T00:00:00Z","timestamp":1674345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u03c0-\u03c0 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.<\/jats:p>","DOI":"10.3390\/ijms24032188","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T02:27:45Z","timestamp":1674440865000},"page":"2188","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["MD Investigation on the Interaction between Carbamazepine and Two CYP Isoforms, CYP3A4 and CYP3A5"],"prefix":"10.3390","volume":"24","author":[{"given":"Shuhui","family":"Liu","sequence":"first","affiliation":[{"name":"Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"},{"name":"School and Hospital of Stomatology, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xu","sequence":"additional","affiliation":[{"name":"School and Hospital of Stomatology, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,22]]},"reference":[{"key":"ref_1","first-page":"CD001769","article-title":"Sodium valproate versus phenytoin monotherapy for epilepsy: An individual participant data review","volume":"8","author":"Nevitt","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1097\/00004714-200304000-00011","article-title":"Antidepressant properties of anticonvulsant drugs for bipolar disorder","volume":"23","author":"Ernst","year":"2003","journal-title":"J. Clin. Psychopharm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1002\/ana.410110312","article-title":"Carbamazepine and hematological monitoring","volume":"11","author":"Hart","year":"1982","journal-title":"Ann. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1172\/JCI113798","article-title":"Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk","volume":"82","author":"Shear","year":"1988","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.1111\/j.1528-1157.1998.tb01679.x","article-title":"Mechanisms of idiosyncratic hypersensitivity reactions to antiepileptic drugs","volume":"39","author":"Leeder","year":"1998","journal-title":"Epilepsia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/BF03256188","article-title":"Carbamazepine-provoked hepatotoxicity and possible aetiopathological role of glutathione in the events. Retrospective review of old data and call for new investigation","volume":"21","author":"Kalapos","year":"2002","journal-title":"Advers. Drug React. Toxicol. Rev."},{"key":"ref_7","first-page":"503","article-title":"Anticonvulsant hypersensitivity syndrome with fatal outcome","volume":"12","author":"Maldonado","year":"2002","journal-title":"Eur. J. Dermatol."},{"key":"ref_8","first-page":"234","article-title":"Epitope mapping studies with human anti-cytochrome P450 3A antibodies","volume":"49","author":"Leeder","year":"1996","journal-title":"Mol. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"17448","DOI":"10.1021\/bi9808464","article-title":"Identification of the heme-modified peptides from cumene hydroperoxide-inactivated cytochrome P450 3A4","volume":"37","author":"He","year":"1998","journal-title":"Biochemistry-US"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1124\/dmd.107.016501","article-title":"CYP3A4-mediated carbamazepine (CBZ) metabolism: Formation of a covalent CBZ-CYP3A4 adduct and alteration of the enzyme kinetic profile","volume":"36","author":"Kang","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1021\/tx980058f","article-title":"Role of drug disposition in drug hypersensitivity: A chemical, molecular, and clinical perspective","volume":"11","author":"Park","year":"1998","journal-title":"Chem. Res. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"80","DOI":"10.2165\/00003088-198510010-00004","article-title":"Carbamazepine metabolism in man. Induction and pharmacogenetic aspects","volume":"10","author":"Eichelbaum","year":"1985","journal-title":"Clin. Pharmacokinet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1124\/dmd.104.001313","article-title":"Evidence of significant contribution from CYP3A5 to hepatic drug metabolism","volume":"32","author":"Huang","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/jnr.24133","article-title":"Association of CYP2R1 rs10766197 with MS risk and disease progression","volume":"96","author":"Scazzone","year":"2018","journal-title":"J. Neurosci. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1097\/FPC.0b013e328348c6f2","article-title":"PharmGKB summary: Carbamazepine pathway","volume":"21","author":"Thorn","year":"2011","journal-title":"Pharmacogenet. Genom."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.pharmtox.39.1.1","article-title":"Cytochrome P-450 3A4: Regulation and role in drug metabolism","volume":"39","author":"Guengrich","year":"1999","journal-title":"Annu. Rev. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17543","DOI":"10.1074\/jbc.M110.198515","article-title":"CYP3A4 mediates growth of estrogen receptor-positive breast cancer cells in part by inducing nuclear translocation of phospho-Stat3 through biosynthesis of (\u00b1) -14,15-epoxyeicosatrienoic acid (EET)","volume":"286","author":"Mitra","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1006\/bbrc.1999.0960","article-title":"Human prostate CYP3A5: Identification of a unique 5\u2032-untranslated sequence and characterization of purified recombinant protein","volume":"260","author":"Yamakoshi","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1002\/pros.22940","article-title":"CYP3A5 regulates prostate cancer cell growth by facilitating nuclear translocation of AR","volume":"75","author":"Mitra","year":"2015","journal-title":"Prostate"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1158\/0008-5472.CAN-14-1589","article-title":"CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2\/Akt Signaling","volume":"75","author":"Jiang","year":"2015","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.2174\/1389200218666170531112038","article-title":"Differential Regulation of CYP3A4 and CYP3A5 and Its Implication in Drug Discovery","volume":"18","author":"Lolodi","year":"2017","journal-title":"Curr. Drug Metab."},{"key":"ref_22","unstructured":"(2008). Discovery Studio 3.1, Accelrys."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1002\/jcc.10306","article-title":"Detailed analysis of grid-based molecular docking: A case study of CDOCKER\u2014A CHARMm-based MD docking algorithm","volume":"24","author":"Wu","year":"2003","journal-title":"J. Comput. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber biomolecular simulation programs","volume":"26","author":"Case","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general amber force field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1002\/jcc.21922","article-title":"Quantum mechanically derived AMBER-compatible heme parameters for various states of the cytochrome P450 catalytic cycle","volume":"33","author":"Shahrokh","year":"2012","journal-title":"J. Comput. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/0010-4655(96)00016-1","article-title":"Ewald summation techniques in perspective: A survey","volume":"95","author":"Toukmaji","year":"1996","journal-title":"Comput. Phys. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1103\/PhysRevA.31.1695","article-title":"Canonical Dynamics: Equilibrium phase-space distributions","volume":"31","author":"Hoover","year":"1985","journal-title":"Phys. Rev. A"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4613","DOI":"10.1063\/1.470648","article-title":"Constant pressure molecular dynamics simulation: The Langevin piston method","volume":"103","author":"Feller","year":"1995","journal-title":"J. Chem. Phys."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1021\/ct400341p","article-title":"PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data","volume":"9","author":"Roe","year":"2013","journal-title":"J. Chem. Theory Comput."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2188\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:13:21Z","timestamp":1760120001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,22]]},"references-count":32,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032188"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032188","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,22]]}}}