In silico screening and molecular dynamic simulations of FDA-approved drugs as an inhibitor of trypanothione reductase of Leishmania donovani

Abstract

Visceral leishmaniasis (VL) is mainly caused by Leishmania donovani (Ld) and Leishmania (L.) infantum, and it is prevalent in Brazil, India and East Africa. VL is a serious health issue, affecting millions of people worldwide and causing thousands of deaths annually. The current treatments for leishmaniasis are inadequate because of their low efficacy, toxicity and growing resistance, underscoring the pressing need to explore new drugs.

Among the various molecular targets explored, trypanothione reductase (TR) is of special relevance because of its crucial function in regulating the parasite's redox homeostasis. Inhibiting TR can disrupt the redox homeostasis of the parasites, offering a promising strategy for developing new drugs with improved efficacy and safety profiles. In this study, 3D structure model of TR was elucidated by homology modelling and potential novel inhibitors against Leishmania donovani TR (LdTR) were identified by performing high-throughput virtual screening of 1615 FDA-approved drugs from the ZINC database via molecular docking, selecting top ligands on the basis of their high binding score and number of hydrogen bonds. These best hits are further subjected to Molecular Dynamics (MD) simulation and Molecular Mechanics Poisson- Boltzmann Surface Area (MM-PBSA) analysis. The results indicated that the binding scores of Dasatinib, Regorafenib, Bicalutamide, Raloxifene and Silodosin are −10.9 and −10.6, −10.1, −9.7 and −9.6 kcal/mol respectively. The lead compounds i.e. Dasatinib, Regorafenib, Bicalutamide, Raloxifene and Silodosin complexes with our target TR were found to be stable during MD simulation studies. Furthermore, MM-PBSA analysis demonstrated that these compounds had a high negative binding free energy. Thus, in-silico results showed that Dasatinib, Regorafenib, Bicalutamide and Raloxifene and Silodosin seem to have efficacy against TR for the treatment of VL. With further in vitro and in vivo investigations Dasatinib, Regorafenib, Bicalutamide, Raloxifene and Silodosin could be a good candidate of choice for combating leishmaniasis.