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Identification of novel inhibitors against UDP‐galactopyranose mutase to combat leishmaniasis
Author(s) -
Kashif Mohammad,
Tabrez Shams,
Husein Atahar,
Arish Mohd,
Kalaiarasan Ponnusamy,
Manna Partha P.,
Subbarao Naidu,
Akhter Yusuf,
Rub Abdur
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26433
Subject(s) - leishmania , leishmaniasis , biology , leishmania donovani , miltefosine , mutase , leishmania major , visceral leishmaniasis , in vitro , trypanosoma cruzi , biochemistry , virology , parasite hosting , enzyme , immunology , world wide web , computer science
Leishmania, a protozoan parasite that causes leishmaniasis, affects 1‐2 million people every year worldwide. Leishmaniasis is a vector born disease and characterized by a diverse group of clinical syndromes. Current treatment is limited because of drug resistance, high cost, poor safety, and low efficacy. The urgent need for potent agents against Leishmania has led to significant advances in the development of novel antileishmanial drugs. β‐galactofuranose (β‐Galf) is an important component of Leishmanial cell surface matrix and plays a critical role in the pathogenesis of parasite. UDP‐galactopyranose mutase (UGM) converts UDP‐galactopyranose (UDP‐Galp) to UDP‐galactofuranose (UDP‐Galf) which acts as the precursor for β‐Galf synthesis. Due to its absence in human, this enzyme is selected as the potential target in search of new antileishmanial drugs. Three dimensional protein structure model of Leishmania major UGM ( Lm UGM) has been homology modeled using Trypanosoma cruzi UGM ( Tc UGM) as a template. The stereochemistry was validated further. We selected already reported active compounds from PubChem database to target the Lm UGM. Three compounds (6064500, 44570814, and 6158954) among the top hit occupied the UDP binding site of UGM suggested to work as a possible inhibitor for it. In vitro antileishmanial activity assay was performed with the top ranked inhibitor, 6064500. The 6064500 molecule has inhibited the growth of Leishmania donovani promastigotes significantly. Further, at similar concentrations it has exhibited significantly lesser toxicity than standard drug miltefosine hydrate in mammalian cells.