Potential targetability of Leishmania donovani proteins to anti-retroviral Amprenavir and Darunavir: an in silico drug repurposing analysis

Lethal Kala-azar, or visceral leishmaniasis, is the infective outcome of intracellular Leishmania donovani to its sole reservoir, the humans, mainly in the tropics, with an annual mortality of ~ 50,000. To date, the treatment regimen includes antimony compounds, miltefosine, amphotericin B, and paramomycin with region-specific effectiveness and mild to severe life-threatening side effects like cardiotoxicity, nephrotoxicity, pancreatitis, myocarditis, and ototoxicity. To solve these harms, alternative drugs have been proposed through computational biology and drug repurposing. In the present study, protein-drug docking analyses of forty-five proteins were performed comparing the structurally similar amino acid side chains in their 3D-crystal structures using SPRITE and ASSAM. Further, to validate the effectiveness of the predicted drugs, their association with the conserved active sites of thirty leishmanial enzymes was studied using GASS. Results delivered two known potent anti-HIV drugs, viz., Amprenavir and Darunavir. These two drugs targeted almost all the candidate proteins with maximum unique binding interfaces. Hence, therapeutic treatments with a combination of these two may effectively intervene with L. donovani proteins and eventually its life cycle.