6CR2

Crystal structure of sterol 14-alpha demethylase (CYP51B) from Aspergillus fumigatus in complex with the VNI derivative N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzamide

Summary for 6CR2

• Entry DOI: 10.2210/pdb6cr2/pdb
• Descriptor: 14-alpha sterol demethylase Cyp51B, PROTOPORPHYRIN IX CONTAINING FE, N-[(1R)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl]-4-{5-[2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3,4-oxadiazol-2-yl}benzamide, ... (4 entities in total)
• Functional Keywords: sterol 14-alpha demethylase (cyp51), cytochrome p450 fold, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Aspergillus fumigatus (Aspergillus fumigatus)
• Total number of polymer chains: 2
• Total formula weight: 110741.43

Authors

Friggeri, L.,Hargrove, T.Y.,Wawrzak, Z.,Lepesheva, G.I. (deposition date: 2018-03-16, release date: 2018-06-27, Last modification date: 2023-10-04)

Primary citation

Friggeri, L.,Hargrove, T.Y.,Wawrzak, Z.,Blobaum, A.L.,Rachakonda, G.,Lindsley, C.W.,Villalta, F.,Nes, W.D.,Botta, M.,Guengerich, F.P.,Lepesheva, G.I.
Sterol 14 alpha-Demethylase Structure-Based Design of VNI (( R)- N-(1-(2,4-Dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives To Target Fungal Infections: Synthesis, Biological Evaluation, and Crystallographic Analysis.
J. Med. Chem., 61:5679-5691, 2018

PubMed Abstract: Because of the increase in the number of immunocompromised patients, the incidence of invasive fungal infections is growing, but the treatment efficiency remains unacceptably low. The most potent clinical systemic antifungals (azoles) are the derivatives of two scaffolds: ketoconazole and fluconazole. Being the safest antifungal drugs, they still have shortcomings, mainly because of pharmacokinetics and resistance. Here, we report the successful use of the target fungal enzyme, sterol 14α-demethylase (CYP51), for structure-based design of novel antifungal drug candidates by minor modifications of VNI [( R)- N-(1-(2,4-dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)], an inhibitor of protozoan CYP51 that cures Chagas disease. The synthesis of fungi-oriented VNI derivatives, analysis of their potencies to inhibit CYP51s from two major fungal pathogens ( Aspergillus fumigatus and Candida albicans), microsomal stability, effects in fungal cells, and structural characterization of A. fumigatus CYP51 in complexes with the most potent compound are described, offering a new antifungal drug scaffold and outlining directions for its further optimization.

PubMed: 29894182
DOI: 10.1021/acs.jmedchem.8b00641

Experimental method

X-RAY DIFFRACTION (2.38 Å)