Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment
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,...
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Format: | Article |
Language: | English |
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MDPI AG
2022-06-01
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Series: | International Journal of Molecular Sciences |
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Online Access: | https://www.mdpi.com/1422-0067/23/13/7291 |
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author | Eric R. Samuels Irina F. Sevrioukova |
author_facet | Eric R. Samuels Irina F. Sevrioukova |
author_sort | Eric R. Samuels |
collection | DOAJ |
description | 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. |
first_indexed | 2024-03-09T21:48:48Z |
format | Article |
id | doaj.art-498f965c37c147179add54bb8153925a |
institution | Directory Open Access Journal |
issn | 1661-6596 1422-0067 |
language | English |
last_indexed | 2024-03-09T21:48:48Z |
publishDate | 2022-06-01 |
publisher | MDPI AG |
record_format | Article |
series | International Journal of Molecular Sciences |
spelling | doaj.art-498f965c37c147179add54bb8153925a2023-11-23T20:11:20ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012313729110.3390/ijms23137291Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine AttachmentEric R. Samuels0Irina F. Sevrioukova1Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, USADepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USAControlled 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.https://www.mdpi.com/1422-0067/23/13/7291CYP3A4inhibitor designritonavir analoguescrystal structurestructure–activity relationship |
spellingShingle | Eric R. Samuels Irina F. Sevrioukova Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment International Journal of Molecular Sciences CYP3A4 inhibitor design ritonavir analogues crystal structure structure–activity relationship |
title | Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment |
title_full | Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment |
title_fullStr | Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment |
title_full_unstemmed | Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment |
title_short | Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment |
title_sort | interaction of cyp3a4 with rationally designed ritonavir analogues impact of steric constraints imposed on the heme ligating group and the end pyridine attachment |
topic | CYP3A4 inhibitor design ritonavir analogues crystal structure structure–activity relationship |
url | https://www.mdpi.com/1422-0067/23/13/7291 |
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