In silico analysis of Leishmania proteomes and protein-protein interaction network: Prioritizing therapeutic targets and drugs for repurposing to treat leishmaniasis

Abstract

Leishmaniasis is a serious world health problem and its current therapies have several limitations demanding to develop novel therapeutics for this disease. The present study aims to prioritize novel broad-spectrum targets using proteomics and protein-protein interaction network (PPIN) data for 11 Leishmania species. Proteome comparison and host non-homology analysis resulted in 3605 pathogen-specific conserved core proteins. Gene ontology analysis indicated their involvement in major molecular functions like DNA binding, transportation, dioxygenase, and catalytic activity. PPIN analysis of these core proteins identified eight hub proteins (viz., vesicle-trafficking protein (LBRM2903_190011800), ribosomal proteins S17 (LBRM2903_34004790) and L2 (LBRM2903_080008100), eukaryotic translation initiation factor 3 (LBRM2903_350086700), replication factor A (LBRM2903_150008000), U3 small nucleolar RNA-associated protein (LBRM2903_340025600), exonuclease (LBRM2903_200021800), and mitochondrial RNA ligase (LBRM2903_200074100)). Among the hub proteins, six were classified as drug targets and two as vaccine candidates. Further, druggability analysis indicated three hub proteins, namely eukaryotic translation initiation factor 3, ribosomal proteins S17 and L2 as druggable. Their three-dimensional structures were modelled and docked with the identified ligands (2-methylthio-N6-isopentenyl-adenosine-5′-monophosphate, artenimol and omacetaxine mepesuccinate). These ligands could be experimentally validated (in vitro and in vivo) and repurposed for the development of novel antileishmanial agents.