4g7g | pdb_00004g7g

Sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei in complex with the VNI derivative (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide [VNI/VNF (VFV)]

spinqualitylabelsall models 4g7g, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4g7g is a 4 chain structure with sequence from Trypanosoma brucei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.05Å Ligands: HEM, VFV Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q385E8_TRYB2 Publication Abstract from PubMed Sterol 14alpha-demethylases (CYP51) are the enzymes essential for sterol biosynthesis. They serve as clinical targets for antifungal azoles and are considered as targets for treatment of human Trypanosomatidae infections. Recently, we have shown that VNI, a potent and selective inhibitor of trypanosomal CYP51 that we identified and structurally characterized in complex with the enzyme, can cure the acute and chronic forms of Chagas disease. The purpose of this work was to apply the CYP51 structure/function for further development of the VNI scaffold. As anticipated, VFV, the derivative designed to fill the deepest portion of the CYP51 substrate binding cavity, reveals a broader antiprotozoan spectrum of action. It has stronger antiparasitic activity in cellular experiments, cures the experimental Chagas disease with 100% efficacy, and suppresses visceral leishmaniasis by 89% (vs. 60% for VNI). Oral bioavailability, low off-target activity, favorable pharmacokinetics and tissue distribution characterize VFV as a promising new drug candidate. VFV as a new effective CYP51 structure-derived drug candidate for Chagas disease and visceral leishmaniasis.,Lepesheva GI, Hargrove TY, Rachakonda G, Wawrzak Z, Pomel S, Cojean S, Nde PN, Nes WD, Locuson CW, Calcutt MW, Waterman MR, Daniels JS, Loiseau PM, Villalta F J Infect Dis. 2015 Apr 15. pii: jiv228. PMID:25883390 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cytochrome P450 3D structures

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