7UFC

Human CYP3A4 bound to an inhibitor

7UFC の概要

• エントリーDOI: 10.2210/pdb7ufc/pdb
• 分子名称: Cytochrome P450 3A4, PROTOPORPHYRIN IX CONTAINING FE, (2R)-3-phenyl-2-({(2S)-3-phenyl-2-[3-(pyridin-3-yl)propanamido]propyl}sulfanyl)-N-[2-(pyridin-3-yl)ethyl]propanamide, ... (4 entities in total)
• 機能のキーワード: cyp3a4, inhibitor, complex, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 56927.03

構造登録者

Sevrioukova, I.F. (登録日: 2022-03-22, 公開日: 2022-07-27, 最終更新日: 2023-10-18)

主引用文献

Samuels, E.R.,Sevrioukova, I.F.
Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment.
Int J Mol Sci, 23:-, 2022

PubMed Abstract: 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.

PubMed: 35806297
DOI: 10.3390/ijms23137291

実験手法

X-RAY DIFFRACTION (2.35 Å)