Identification of potential inhibitors targeted for strengthening search of anti-leishmanial therapeutics

Abstract

Visceral leishmaniasis (VL: a fatal disease) is reported to occur at the rate of 70,000 to 90,000 per year, according to WHO. VL is caused by Leishmania donovani species causing 90% cases of VL. Current treatment regime is not satisfactory due to substantial toxic side effects of existing antileishmanial therapy and the emergence of drug resistance from different part of the world. These issues make existing therapy unsuitable management of VL. There are various studies dedicated to overcoming the shortcomings in antileishmanial therapeutics. Likewise, in this study, we have targeted HSP100 (heat shock protein) of L. donovani for identification of potent antileishmanial. HSP100 protein is released when the Leishmania parasite encounters heat stress in macrophage of mammalian host making it an effective target. This in silico study was carried out with 10 unexplored ligands and Miltefosine (an established anti-leishmanial drug used as control) via targeting L. donovani HSP100. We report that two test ligands Diospyrin and Benzoxaborole had outstanding docking potential with L. donovani HSP100 and were chosen for further analysis of drug-likeness and ADMET (absorption distribution, metabolism, and excretion) properties. These two ligands docking scores were better than the antileishmanial Miltefosine and had better ADMET properties as a drug candidate. The result gave us a lead and confirmation to support our hypothesis that HSP100 can be a potential drug target of L. donovani and Diospyrin and Benzoxaborole can be potent antileishmanial molecules.