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

Sevrioukova IF, Poulos TL
J Med Chem 56 3733-41 (2013)
Related entries: 4i3q, 4i4g

Cited: 32 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 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.

Reviews - 4i4h mentioned but not cited (1)

  1. Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions. Sevrioukova IF, Poulos TL. Adv Exp Med Biol 851 83-105 (2015)

Articles - 4i4h mentioned but not cited (5)

  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. Pyridine-substituted desoxyritonavir is a more potent inhibitor of cytochrome P450 3A4 than ritonavir. Sevrioukova IF, Poulos TL. J Med Chem 56 3733-3741 (2013)
  3. The X-Ray Crystal Structure of the Human Mono-Oxygenase Cytochrome P450 3A5-Ritonavir Complex Reveals Active Site Differences between P450s 3A4 and 3A5. Hsu MH, Savas U, Johnson EF. Mol Pharmacol 93 14-24 (2018)
  4. Four Major Channels Detected in the Cytochrome P450 3A4: A Step toward Understanding Its Multispecificity. Benkaidali L, André F, Moroy G, Tangour B, Maurel F, Petitjean M. Int J Mol Sci 20 E987 (2019)
  5. The Development of Target-Specific Pose Filter Ensembles To Boost Ligand Enrichment for Structure-Based Virtual Screening. Xia J, Hsieh JH, Hu H, Wu S, Wang XS. J Chem Inf Model 57 1414-1425 (2017)


Reviews citing this publication (4)

  1. 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)
  2. 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)
  3. Spectroscopic studies of the cytochrome P450 reaction mechanisms. Mak PJ, Denisov IG. Biochim Biophys Acta Proteins Proteom 1866 178-204 (2018)
  4. CYP2J2 Molecular Recognition: A New Axis for Therapeutic Design. Das A, Weigle AT, Arnold WR, Kim JS, Carnevale LN, Huff HC. Pharmacol Ther 215 107601 (2020)

Articles citing this publication (22)

  1. 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)
  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. 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)
  4. Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5. Wright WC, Chenge J, Wang J, Girvan HM, Yang L, Chai SC, Huber AD, Wu J, Oladimeji PO, Munro AW, Chen T. J Med Chem 63 1415-1433 (2020)
  5. Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213. Denisov IG, Grinkova YV, Nandigrami P, Shekhar M, Tajkhorshid E, Sligar SG. Biochemistry 58 1411-1422 (2019)
  6. Inhibition of Human CYP3A4 by Rationally Designed Ritonavir-Like Compounds: Impact and Interplay of the Side Group Functionalities. Samuels ER, Sevrioukova I. Mol Pharm 15 279-288 (2018)
  7. Structure-Activity Relationships of Rationally Designed Ritonavir Analogues: Impact of Side-Group Stereochemistry, Headgroup Spacing, and Backbone Composition on the Interaction with CYP3A4. Samuels ER, Sevrioukova I. Biochemistry 58 2077-2087 (2019)
  8. A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4. Panneerselvam S, Yesudhas D, Durai P, Anwar MA, Gosu V, Choi S. Molecules 20 14915-14935 (2015)
  9. Interaction of Human Drug-Metabolizing CYP3A4 with Small Inhibitory Molecules. Sevrioukova I. Biochemistry 58 930-939 (2019)
  10. Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength. Samuels ER, Sevrioukova IF. Int J Mol Sci 22 E852 (2021)
  11. Structural Perspectives of the CYP3A Family and Their Small Molecule Modulators in Drug Metabolism. Wright WC, Chenge J, Chen T. Liver Res 3 132-142 (2019)
  12. Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4. Toupin N, Steinke SJ, Nadella S, Li A, Rohrabaugh TN, Samuels ER, Turro C, Sevrioukova IF, Kodanko JJ. J Am Chem Soc 143 9191-9205 (2021)
  13. Probing membrane enhanced protein-protein interactions in a minimal redox complex of cytochrome-P450 and P450-reductase. Mahajan M, Ravula T, Prade E, Anantharamaiah GM, Ramamoorthy A. Chem Commun (Camb) 55 5777-5780 (2019)
  14. An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4. Samuels ER, Sevrioukova IF. Bioorg Med Chem 28 115349 (2020)
  15. The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia. Caffall ZF, Wilkes BJ, Hernández-Martinez R, Rittiner JE, Fox JT, Wan KK, Shipman MK, Titus SA, Zhang YQ, Patnaik S, Hall MD, Boxer MB, Shen M, Li Z, Vaillancourt DE, Calakos N. Sci Transl Med 13 eabd3904 (2021)
  16. Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies. Li J, Chen Y, Tang Y, Li W, Tu Y. J Chem Inf Model 61 2418-2426 (2021)
  17. Mechanistic Insights into the Regio- and Stereoselectivities of Testosterone and Dihydrotestosterone Hydroxylation Catalyzed by CYP3A4 and CYP19A1. Li J, Tang Y, Li W, Tu Y. Chemistry 26 6214-6223 (2020)
  18. Structure-guided manipulation of the regioselectivity of the cyclosporine A hydroxylase CYP-sb21 from Sebekia benihana. Li F, Ma L, Zhang X, Chen J, Qi F, Huang Y, Qu Z, Yao L, Zhang W, Kim ES, Li S. Synth Syst Biotechnol 5 236-243 (2020)
  19. The Cytochrome P450 3A4 has three Major Conformations: New Clues to Drug Recognition by this Promiscuous Enzyme. Benkaidali L, André F, Moroy G, Tangour B, Maurel F, Petitjean M. Mol Inform 36 (2017)
  20. Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment. Samuels ER, Sevrioukova IF. Int J Mol Sci 23 7291 (2022)
  21. Correction to "Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213". Denisov IG, Grinkova YV, Nandigrami P, Shekhar M, Tajkhorshid E, Sligar SG. Biochemistry 58 2796 (2019)
  22. Transgenic Expression of Haemonchus contortus Cytochrome P450 Hco-cyp-13A11 Decreases Susceptibility to Particular but Not All Macrocyclic Lactones in the Model Organism Caenorhabditis elegans. Jakobs N, Yilmaz E, Krücken J. Int J Mol Sci 23 9155 (2022)


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