title: Pyridine-substituted desoxyritonavir is a more potent inhibitor of cytochrome P450 3A4 than ritonavir.
abstract: Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.
authors.affiliation: Departments of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, United States. sevrioui@uci.edu
authors.forename: Irina F
authors.initials: IF
authors.lastname: Sevrioukova
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Poulos
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004795:Enzyme Stability / Q000187:drug effects; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry*; D019438:Ritonavir / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D011725:Pyridines; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir