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Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength.

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Samuels ER, Sevrioukova IF
OpenAccess logo Int J Mol Sci 22 (2021)
Related entries: 7kvh, 7kvi, 7kvj, 7kvk, 7kvm, 7kvn, 7kvo, 7kvq, 7kvs

Cited: 10 times
EuropePMC logo PMID: 33467005

Abstract

Inhibition of the major human drug-metabolizing cytochrome P450 3A4 (CYP3A4) by pharmaceuticals and other xenobiotics could lead to toxicity, drug-drug interactions and other adverse effects, as well as pharmacoenhancement. Despite serious clinical implications, the structural basis and attributes required for the potent inhibition of CYP3A4 remain to be established. We utilized a rational inhibitor design to investigate the structure-activity relationships in the analogues of ritonavir, the most potent CYP3A4 inhibitor in clinical use. This study elucidated the optimal length of the head-group spacer using eleven (series V) analogues with the R1/R2 side-groups as phenyls or R1-phenyl/R2-indole/naphthalene in various stereo configurations. Spectral, functional and structural characterization of the inhibitory complexes showed that a one-atom head-group linker elongation, from pyridyl-ethyl to pyridyl-propyl, was beneficial and markedly improved Ks, IC50 and thermostability of CYP3A4. In contrast, a two-atom linker extension led to a multi-fold decrease in the binding and inhibitory strength, possibly due to spatial and/or conformational constraints. The lead compound,

Articles - 7kvp mentioned but not cited (1)

  1. 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)


Reviews citing this publication (2)

  1. Improving Curcumin Bioavailability: Current Strategies and Future Perspectives. Tabanelli R, Brogi S, Calderone V. Pharmaceutics 13 1715 (2021)
  2. The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism? Loos NHC, Beijnen JH, Schinkel AH. Int J Mol Sci 23 9866 (2022)

Articles citing this publication (7)

  1. 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)
  2. Innovative C2-symmetric testosterone and androstenedione dimers: Design, synthesis, biological evaluation on prostate cancer cell lines and binding study to recombinant CYP3A4. Paquin A, Oufqir Y, Sevrioukova IF, Reyes-Moreno C, Bérubé G. Eur J Med Chem 220 113496 (2021)
  3. Structural Basis for the Diminished Ligand Binding and Catalytic Ability of Human Fetal-Specific CYP3A7. Sevrioukova IF. Int J Mol Sci 22 5831 (2021)
  4. Crystal Structure of CYP3A4 Complexed with Fluorol Identifies the Substrate Access Channel as a High-Affinity Ligand Binding Site. Sevrioukova IF. Int J Mol Sci 23 12591 (2022)
  5. 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)
  6. Silibinin Suppresses the Hyperlipidemic Effects of the ALK-Tyrosine Kinase Inhibitor Lorlatinib in Hepatic Cells. Verdura S, Encinar JA, Fernández-Arroyo S, Joven J, Cuyàs E, Bosch-Barrera J, Menendez JA. Int J Mol Sci 23 9986 (2022)
  7. Investigating a new C2-symmetric testosterone dimer and its dihydrotestosterone analog: Synthesis, antiproliferative activity on prostate cancer cell lines and interaction with CYP3A4. Paquin A, Fortin L, Girouard J, Reyes-Moreno C, Sevrioukova IF, Bérubé G. Eur J Med Chem 250 115222 (2023)


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