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Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferase

DOI: 10.1039/C5MD00242G DOI Help

Authors: Zhiyong Yu (Imperial College London) , James A. Brannigan (University of York) , Kaveri Rangachari (The Francis Crick Institute) , William P. Heal (Imperial College London) , Anthony Wilkinson (University of York) , Anthony A. Holder (The Francis Crick Institute) , Robin J. Leatherbarrow (Imperial College London) , Edward W. Tate (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Medchemcomm

State: Published (Approved)
Published: August 2015
Diamond Proposal Number(s): 7864 , 1221

Abstract: N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19. This molecule exhibited improved enzyme and cellular potency, and reduced lipophilicity compared to inhibitor 3. Further structure-based inhibitor design led to the discovery of 30, the most potent inhibitor in this series, which showed single-digit nM enzyme affinity and sub-μM anti-plasmodial activity

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography