5ajr

Sterol 14-alpha demethylase (CYP51) from Trypanosoma cruzi in complex with the 1-tetrazole derivative VT-1161 ((R)-2-(2,4-Difluorophenyl)-1, 1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl) pyridin-2-yl)propan-2-ol)

spinqualitylabelsall models 5ajr, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ajr is a 1 chain structure with sequence from Trypanosoma cruzi. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.75Å Ligands: HEM, VT1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CP51_TRYCC Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol (By similarity). Favors C4 dimethylated substrates, the substrate preference order is 24-methylenedihydrolanosterol > 24,25-dihydrolanosterol > lanosterol > obtusifoliol > norlanosterol. [UniProtKB:P0A512] Publication Abstract from PubMed A novel antifungal drug candidate, 1-tetrazole VT-1161 [(R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trif luoroethoxy)phenyl)pyridin-2-yl)propan-2-ol], which is currently in two Phase 2b antifungal clinical trials, was found to be a tight-binding ligand (the apparent dissociation constant (Kd) = 24 nM) and a potent inhibitor of cytochrome P450 sterol 14alpha-demethylase (CYP51) from the protozoan pathogen Trypanosoma cruzi. Moreover, VT-1161 revealed high antiparasitic efficiency in cellular experiments against amastigotes of the Tulahuen strain of T. cruzi (EC50=2.5 nM) and was active in vivo, causing >99.8% of peak parasitemia suppression in a mouse model of infection with the naturally drug-resistant Y strain of the parasite. The data strongly support the potential utility of VT-1161 in the treatment of Chagas disease. Structural characterization of T. cruzi CYP51 in complex with VT-1161 provides insights into the molecular basis for the compound inhibitory potency and paves the way for further rational development of this novel, tetrazole-based inhibitory chemotype, both for antiprotozoan, and for antifungal chemotherapy. Antiparasitic effect in vitro, activity in a murine model of Chagas disease, and structural characterization in complex with the target enzyme CYP51 from Trypanosoma cruzi of the potent clinical candidate VT-1161.,Hoekstra WJ, Hargrove TY, Wawrzak Z, Batista DD, da Silva CF, Nefertiti AS, Rachakonda G, Schotzinger RJ, Villalta F, Soeiro MN, Lepesheva GI Antimicrob Agents Chemother. 2015 Dec 7. pii: AAC.02287-15. PMID:26643331 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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