Discovery of high affinity inhibitors of Leishmania donovani N-myristoyltransferase

Mark D. Rackham; Zhiyong Yu; James A. Brannigan; William P. Heal; Daniel Paape; K. Victoria Barker; Anthony J. Wilkinson; Deborah F. Smith; Robin J. Leatherbarrow; Edward W. Tate

doi:10.1039/C5MD00241A

Discovery of high affinity inhibitors of Leishmania donovani N-myristoyltransferase†

Mark D. Rackham,‡§^a Zhiyong Yu,‡¶^a James A. Brannigan,^b William P. Heal,||^a Daniel Paape,**^c K. Victoria Barker,††^a Anthony J. Wilkinson,^b Deborah F. Smith,^c Robin J. Leatherbarrow ‡‡^a and Edward W. Tate*^a

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^a Department of Chemistry, Imperial College London, South Kensington Campus, London, UK
E-mail: e.tate@imperial.ac.uk
Tel: +44 (0) 2075 943752

^b Structural Biology Laboratory, Department of Chemistry, University of York, York, UK

^c Department of Biology, University of York, York, UK

Abstract

N-Myristoyltransferase (NMT) is a potential drug target in Leishmania parasites. Scaffold-hopping from published inhibitors yielded the serendipitous discovery of a chemotype selective for Leishmania donovani NMT; development led to high affinity inhibitors with excellent ligand efficiency. The binding mode was characterised by crystallography and provides a structural rationale for selectivity.

MedChemComm

Discovery of high affinity inhibitors of Leishmania donovani N-myristoyltransferase†

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Discovery of high affinity inhibitors of Leishmania donovani N-myristoyltransferase

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