Febrifugine analogues as Leishmania donovani trypanothione reductase inhibitors: binding energy analysis assisted by molecular docking, ADMET and molecular dynamics simulation

Abstract

Visceral leishmaniasis affects people from 70 countries worldwide, mostly from Indian, African and south American continent. The increasing resistance to antimonial, miltefosine and frequent toxicity of amphotericin B drives an urgent need to develop an antileishmanial drug with excellent efficacy and safety profile. In this study we have docked series of febrifugine analogues (n = 8813) against trypanothione reductase in three sequential docking modes. Extra precision docking resulted into 108 ligands showing better docking score as compared to two reference ligand. Furthermore, 108 febrifugine analogues and reference inhibitor clomipramine were subjected to ADMET, QikProp and molecular mechanics, the generalized born model and solvent accessibility study to ensure the toxicity caused by compounds and binding-free energy, respectively. Two best ligands (FFG7 and FFG2) qualifying above screening parameters were further subjected to molecular dynamics simulation. Conducting these studies, here we confirmed that 6-chloro-3-[3-(3-hydroxy-2-piperidyl)-2-oxo-propyl]-7-(4-pyridyl) quinazolin-4-one can be potential drug candidate to fight against Leishmania donovani parasites.

Keywords:

• molecular docking
• molecular dynamics
• trypanothione reductase
• ROC curve
• visceral leishmaniasis

Acknowledgements

RKP is thankful to Department of Science and Technology for providing INSPIRE fellowship. VKP is thankful to UGC and DST for providing start up grant as well as Central University of Rajasthan for providing Schrodinger, PyMol, Desmond and ADMET predictor facility. BVK is thankful to Indian Institute of Technology Bombay for Post Doctoral fellowship. AK is thankful to Department of Biotechnology for Innovative Young Biotechnologist Award (Grant Number BT/06/IYBA/2012), New Delhi, India.

Disclosure statement

The authors have declared no competing interest.

Additional information

Funding

This work was supported by Department of Biotechnology, India [grant number BT/06/IYBA/2012]; UGC, India [30-66/2014 (BSR)] and SERB-DST [YSS/2015/000716].