8VK6

14alpha-demethylase (CYP51) with amide-linked long arm extension antifungal azole inhibitor

これはPDB形式変換不可エントリーです。

8VK6 の概要

• エントリーDOI: 10.2210/pdb8vk6/pdb
• 分子名称: Lanosterol 14-alpha demethylase, PROTOPORPHYRIN IX CONTAINING FE, N-[(2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4'-(trifluoromethoxy)[1,1'-biphenyl]-4-carboxamide, ... (6 entities in total)
• 機能のキーワード: amide-linked azole inhibitor, cyp51, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Saccharomyces cerevisiae YJM789 (Baker's yeast)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 63769.03

構造登録者

Tyndall, J.D.A.,Monk, B.C.,Simons, C. (登録日: 2024-01-08, 公開日: 2025-01-15, 最終更新日: 2025-07-30)

主引用文献

Alsulaimany, M.,Keniya, M.V.,Alanazi, R.S.,N Ruma, Y.,Hughes, C.S.,Jones, A.T.,Tyndall, J.D.A.,Parker, J.E.,Monk, B.C.,Simons, C.
Exploring Long Arm Amide-Linked Side Chains in the Design of Antifungal Azole Inhibitors of Sterol 14 alpha-Demethylase (CYP51).
J.Med.Chem., 68:10781-10799, 2025

PubMed Abstract: The rise in fungal drug resistance has exacerbated the treatment of invasive fungal infections, most commonly caused by . This research describes the synthesis of extended "long-arm" azole antifungals that were evaluated against wild-type and resistant fungal species. Biphenyl derivative was the most effective derivative, displaying potent inhibitory activity against , , and CYP51 enzymes, including in resistant strains, in comparison with posaconazole. The X-ray crystal structure of - complexed with CYP51 showed a hydrogen bond between the oxygen of the trifluoromethoxy group of and the His381 side chain of CYP51, which is postulated to contribute significantly to its binding, and stabilization in the presence of the CYP51 Y140F/H, and CYP51 Y132F mutations and the K143R mutation. Computational studies and IC evaluation of compound vs wild-type, Y132F, and Y132H/K143 mutant strains supported MIC observations.

PubMed: 40403151
DOI: 10.1021/acs.jmedchem.4c02922

実験手法

X-RAY DIFFRACTION (1.89 Å)