7RKW

Naegleria fowleri CYP51(NfCYP51) complex with (S)-1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl 3,5-dichlorobenzoate

7RKW の概要

• エントリーDOI: 10.2210/pdb7rkw/pdb
• 分子名称: Protein CYP51, PROTOPORPHYRIN IX CONTAINING FE, (1S)-1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl 3,5-dichlorobenzoate, ... (5 entities in total)
• 機能のキーワード: ergosterol biosynthesis, oxidoreductase, azole inhibitors
• 由来する生物種: Naegleria fowleri (Brain eating amoeba)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 54647.78

構造登録者

Sharma, V.,Podust, L.M. (登録日: 2021-07-22, 公開日: 2022-07-27, 最終更新日: 2023-12-27)

主引用文献

Sharma, V.,Madia, V.N.,Tudino, V.,Nguyen, J.V.,Debnath, A.,Messore, A.,Ialongo, D.,Patacchini, E.,Palenca, I.,Basili Franzin, S.,Seguella, L.,Esposito, G.,Petrucci, R.,Di Matteo, P.,Bortolami, M.,Saccoliti, F.,Di Santo, R.,Scipione, L.,Costi, R.,Podust, L.M.
Miconazole-like Scaffold is a Promising Lead for Naegleria fowleri -Specific CYP51 Inhibitors.
J.Med.Chem., 2023

PubMed Abstract: Developing drugs for brain infection by is an unmet medical need. We used a combination of cheminformatics, target-, and phenotypic-based drug discovery methods to identify inhibitors that target an essential enzyme, sterol 14-demethylase (NfCYP51). A total of 124 compounds preselected were tested against . Nine primary hits with EC ≤ 10 μM were phenotypically identified. Cocrystallization with NfCYP51 focused attention on one primary hit, miconazole-like compound . The -enantiomer of produced a 1.74 Å cocrystal structure. A set of analogues was then synthesized and evaluated to confirm the superiority of the -configuration over the -configuration and the advantage of an ether linkage over an ester linkage. The two compounds, - and -, had an improved EC and compared to . Importantly, both were readily taken up into the brain. The brain-to-plasma distribution coefficient of - was 1.02 ± 0.12, suggesting further evaluation as a lead for primary amoebic meningoencephalitis.

PubMed: 38085955
DOI: 10.1021/acs.jmedchem.3c01898

実験手法

X-RAY DIFFRACTION (1.81 Å)