title: Dirlotapide as a model substrate to refine structure-based drug design strategies on CYP3A4-catalyzed metabolism.
abstract: Multiple crystal structures of CYP3A4 bound with various substrates or inhibitors have been used as templates for docking of new chemical entities to predict sites of metabolism and molecular interactions for drug design. Herein, modeling studies with dirlotapide, a CYP3A4 substrate, indicated that a substantial conformational change of CYP3A4 was necessary to accommodate it within the active site cavity, which is in good agreement with a new published CYP3A4 ritonavir co-crystal structure. Thus, the importance of considering the substrate-induced conformational change in CYP3A4, thermochemical properties of reaction centers, and essential in vitro experimental data support were analyzed for the refinement of computational models.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT 06340, United States. hao.sun@pfizer.com
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bessire
authors.forename: Alfin
authors.initials: A
authors.lastname: Vaz
mesh_terms: D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D002384:Catalysis; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D003460:Crystallization; D018360:Crystallography, X-Ray / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry*; D015195:Drug Design; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008024:Ligands; D013058:Mass Spectrometry / Q000379:methods; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D013696:Temperature
chemical_list: D002219:Carbamates; D007211:Indoles; D008024:Ligands; C521290:dirlotapide; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human