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Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment.
Samuels, Eric R; Sevrioukova, Irina F.
Affiliation
  • Samuels ER; Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA.
  • Sevrioukova IF; Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
Int J Mol Sci ; 23(13)2022 Jun 30.
Article in En | MEDLINE | ID: mdl-35806297
Controlled inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) is utilized to boost bioavailability of anti-viral and immunosuppressant pharmaceuticals. We investigate structure-activity relationships (SARs) in analogues of ritonavir, a potent CYP3A4 inhibitor marketed as pharmacoenhancer, to determine structural elements required for potent inhibition and whether the inhibitory potency can be further improved via a rational structure-based design. This study investigated eight (series VI) inhibitors differing in head- and end-moieties and their respective linkers. SAR analysis revealed the multifactorial regulation of inhibitory strength, with steric constraints imposed on the tethered heme-ligating moiety being a key factor. Minimization of these constraints by changing the linkers' length/flexibility and N-heteroatom position strengthened heme coordination and markedly improved binding and/or inhibitory strength. Impact of the end-pyridine attachment was not uniform due to influence of other determinants controlling the ligand-binding mode. This interplay between pharmacophoric determinants and the end-group enlargement can be used for further inhibitor optimization.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ritonavir / Cytochrome P-450 CYP3A Language: En Journal: Int J Mol Sci Year: 2022 Document type: Article Affiliation country: United States Country of publication: Switzerland

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ritonavir / Cytochrome P-450 CYP3A Language: En Journal: Int J Mol Sci Year: 2022 Document type: Article Affiliation country: United States Country of publication: Switzerland