4D75

Cytochrome P450 3A4 bound to an inhibitor

4D75 の概要

• エントリーDOI: 10.2210/pdb4d75/pdb
• 関連するPDBエントリー: 4D6Z
• 分子名称: CYTOCHROME P450 3A4, tert-butyl {6-oxo-6-[(pyridin-3-ylmethyl)amino]hexyl}carbamate, PROTOPORPHYRIN IX CONTAINING FE, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, monooxygenase, inhibitory complex
• 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: 56579.58

構造登録者

Sevrioukova, I.,Poulos, T. (登録日: 2014-11-19, 公開日: 2015-09-23, 最終更新日: 2023-12-20)

主引用文献

Kaur, P.,Chamberlin, R.,Poulos, T.L.,Sevrioukova, I.F.
Structure-Based Inhibitor Design for Evaluation of a Cyp3A4 Pharmacophore Model.
J.Med.Chem., 59:4210-, 2016

PubMed Abstract: Human cytochrome P450 3A4 (CYP3A4) is a key xenobiotic-metabolizing enzyme that oxidizes and clears the majority of drugs. CYP3A4 inhibition may lead to drug-drug interactions, toxicity, and other adverse effects but, in some cases, could be beneficial and enhance therapeutic efficiency of coadministered pharmaceuticals that are metabolized by CYP3A4. On the basis of our investigations of analogs of ritonavir, a potent CYP3A4 inactivator and pharmacoenhancer, we have built a pharmacophore model for a CYP3A4-specific inhibitor. This study is the first attempt to test this model using a set of rationally designed compounds. The functional and structural data presented here agree well with the proposed pharmacophore. In particular, we confirmed the importance of a flexible backbone, the H-bond donor/acceptor moiety, and aromaticity of the side group analogous to Phe-2 of ritonavir and demonstrated the leading role of hydrophobic interactions at the sites adjacent to the heme and phenylalanine cluster in the ligand binding process. The X-ray structures of CYP3A4 bound to the rationally designed inhibitors provide deeper insights into the mechanism of the CYP3A4-ligand interaction. Most importantly, two of our compounds (15a and 15b) that are less complex than ritonavir have comparable submicromolar affinity and inhibitory potency for CYP3A4 and, thus, could serve as templates for synthesis of second generation inhibitors for further evaluation and optimization of the pharmacophore model.

PubMed: 26371436
DOI: 10.1021/ACS.JMEDCHEM.5B01146

実験手法

X-RAY DIFFRACTION (2.25 Å)