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Issue 90, 2016, Issue in Progress
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Non-competitive inhibitor of nucleoside hydrolase from Leishmania donovani identified by fragment-based drug discovery

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Abstract

Nucleoside hydrolase is an important target for the development of new leishmanicidal agents due to its role in parasite proliferation. Using the principles of fragment-based drug discovery, a library of 111 fragments was assembled for screening by nuclear magnetic resonance using the saturation transfer difference. Five fragments were selected as ligands of Leishmania donovani nucleoside hydrolase (NHLd) and kinetics studies revealed that fragment 3 acts as a new non-competitive inhibitor. Its binding mode was proposed on the basis of molecular docking, using a structural model of NHLd constructed by homology. An intermolecular interaction between fragments 3 and 5 was found by NOESY and docking studies. These data could be used to design more potent NHLd inhibitors and to aid the development of leishmanicidal drugs.

Graphical abstract: Non-competitive inhibitor of nucleoside hydrolase from Leishmania donovani identified by fragment-based drug discovery

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Supplementary files

Article information


Submitted
10 Jun 2016
Accepted
30 Aug 2016
First published
31 Aug 2016

RSC Adv., 2016,6, 87738-87744
Article type
Paper
Author version available

Non-competitive inhibitor of nucleoside hydrolase from Leishmania donovani identified by fragment-based drug discovery

M. A. Alves, C. Nirma, M. M. Moreira, R. O. Soares, P. G. Pascutti, F. Noël, P. R. R. Costa, C. M. R. Sant'Anna, E. J. Barreiro, L. M. Lima and L. W. Tinoco, RSC Adv., 2016, 6, 87738
DOI: 10.1039/C6RA15143D

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