title: Interaction of human cytochrome P4503A4 with ritonavir analogs.
abstract: Ritonavir is a HIV protease inhibitor that also potently inactivates cytochrome P450 3A4 (CYP3A4), a major human drug-metabolizing enzyme. To better understand the mechanism of ligand binding and to find strategies for improvement of the inhibitory potency of ritonavir, currently administered to enhance pharmacokinetics of other anti-HIV drugs that are quickly metabolized by CYP3A4, we compared the manner of CYP3A4 interaction with the drug and two analogs lacking either the heme-ligating thiazole nitrogen or the entire thiazole group. Based on the kinetic, mutagenesis and structural data, we conclude that: (i) the active site residue Arg212 assists binding of all investigated compounds and, thus, may play a more prominent role in metabolic transformation of xenobiotics than previously thought, (ii) peripheral binding of ritonavir limits the heme coordination rate and complicates the binding kinetics, (iii) association of ritonavir-like type II ligands is driven by heme coordination whereas hydrophobic forces define the binding mode, and (iv) substitution of one phenyl group in ritonavir with a smaller hydrophobic moiety could prevent steric clashing and, hence, increase the affinity and inhibitory potency of the drug.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, 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: D001665:Binding Sites; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry*; D004789:Enzyme Activation; D017320:HIV Protease Inhibitors / Q000737:chemistry; D008956:Models, Chemical; D011485:Protein Binding; D019438:Ritonavir / Q000031:analogs & derivatives* / Q000737:chemistry*
chemical_list: D017320:HIV Protease Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019438:Ritonavir