4BJK

CYP51 of Trypanosoma brucei bound to (S)-N-(3-(1H-indol-3-yl)-1-oxo-1- (pyridin-4-ylamino)propan-2-yl)-3,3'-difluoro-(1,1'-biphenyl)-4- carboxamide

Summary for 4BJK

• Entry DOI: 10.2210/pdb4bjk/pdb
• Descriptor: LANOSTEROL 14-ALPHA-DEMETHYLASE, PROTOPORPHYRIN IX CONTAINING FE, 3,3'-difluoro-N-[(2S)-3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl]biphenyl-4-carboxamide, ... (4 entities in total)
• Functional Keywords: oxidoreductase, ergosterol biosynthesis
• Biological source: TRYPANOSOMA BRUCEI
• Total number of polymer chains: 4
• Total formula weight: 216458.30

Authors

Podust, L.M. (deposition date: 2013-04-18, release date: 2013-09-04, Last modification date: 2023-12-20)

Primary citation

Choi, J.Y.,Calvet, C.M.,Gunatilleke, S.S.,Ruiz, C.,Cameron, M.D.,Mckerrow, J.H.,Podust, L.M.,Roush, W.R.
Rational Development of 4-Aminopyridyl-Based Inhibitors Targeting Trypanosoma Cruzi Cyp51 as Anti-Chagas Agents.
J.Med.Chem., 56:7651-, 2013

PubMed Abstract: A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.

PubMed: 24079662
DOI: 10.1021/JM401067S

Experimental method

X-RAY DIFFRACTION (2.67 Å)