Dirlotapide as a model substrate to refine structure-based drug design strategies on CYP3A4-catalyzed metabolism.

Article Details

Citation
Copy to clipboard

Sun H, Bessire AJ, Vaz A

Dirlotapide as a model substrate to refine structure-based drug design strategies on CYP3A4-catalyzed metabolism.

Bioorg Med Chem Lett. 2012 Jan 1;22(1):371-6. doi: 10.1016/j.bmcl.2011.10.121. Epub 2011 Nov 6.

PubMed ID
22094027 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drugs