7RKW
Naegleria fowleri CYP51(NfCYP51) complex with (S)-1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl 3,5-dichlorobenzoate
Summary for 7RKW
| Entry DOI | 10.2210/pdb7rkw/pdb |
| Descriptor | Protein CYP51, PROTOPORPHYRIN IX CONTAINING FE, (1S)-1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl 3,5-dichlorobenzoate, ... (5 entities in total) |
| Functional Keywords | ergosterol biosynthesis, oxidoreductase, azole inhibitors |
| Biological source | Naegleria fowleri (Brain eating amoeba) |
| Total number of polymer chains | 1 |
| Total formula weight | 54647.78 |
| Authors | Sharma, V.,Podust, L.M. (deposition date: 2021-07-22, release date: 2022-07-27, Last modification date: 2023-12-27) |
| Primary citation | 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 Cited by 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: 38085955DOI: 10.1021/acs.jmedchem.3c01898 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.81 Å) |
Structure validation
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