4i4g Citations

Pyridine-substituted desoxyritonavir is a more potent inhibitor of cytochrome P450 3A4 than ritonavir.

J. Med. Chem. (2013)
Related entries: 4i3q, 4i4h

Cited: 7 times
EuropePMC logo PMID: 23586711

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 analogs, 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.

Reviews citing this publication (3)

  1. Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions. Sevrioukova IF, Poulos TL. Adv. Exp. Med. Biol. 851 83-105 (2015)
  2. Structure-based ligand design to overcome CYP inhibition in drug discovery projects. Brändén G, Sjögren T, Schnecke V, Xue Y. Drug Discov. Today 19 905-911 (2014)
  3. Ritonavir analogues as a probe for deciphering the cytochrome P450 3A4 inhibitory mechanism. Sevrioukova IF, Poulos TL. Curr Top Med Chem 14 1348-1355 (2014)

Articles citing this publication (4)

  1. Structure-Based Inhibitor Design for Evaluation of a CYP3A4 Pharmacophore Model. Kaur P, Chamberlin AR, Poulos TL, Sevrioukova IF. J. Med. Chem. 59 4210-4220 (2016)
  2. Intersection of the Roles of Cytochrome P450 Enzymes with Xenobiotic and Endogenous Substrates: Relevance to Toxicity and Drug Interactions. Guengerich FP. Chem. Res. Toxicol. 30 2-12 (2017)
  3. Structural basis for regiospecific midazolam oxidation by human cytochrome P450 3A4. Sevrioukova IF, Poulos TL. Proc. Natl. Acad. Sci. U.S.A. 114 486-491 (2017)
  4. Membrane Fluidity Modulates Thermal Stability and Ligand Binding of Cytochrome P4503A4 in Lipid Nanodiscs. McClary WD, Sumida JP, Scian M, Paço L, Atkins WM. Biochemistry 55 6258-6268 (2016)