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

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.