Comparative Proteomics and Genome-Wide Druggability Analyses Prioritized Promising Therapeutic Targets against Drug-Resistant Leishmania tropica

Abstract

Leishmania tropica is a tropical parasite causing cutaneous leishmaniasis (CL) in humans. Leishmaniasis is a serious public health threat, affecting an estimated 350 million people in 98 countries. The global rise in antileishmanial drug resistance has triggered the need to explore novel therapeutic strategies against this parasite. In the present study, we utilized the recently available multidrug resistant L. tropica strain proteome data repository to identify alternative therapeutic drug targets based on comparative subtractive proteomic and druggability analyses. Additionally, small drug-like compounds were scanned against novel targets based on virtual screening and ADME profiling. The analysis unveiled 496 essential cellular proteins of L. tropica that were nonhomologous to the human proteome set. The druggability analyses prioritized nine parasite-specific druggable proteins essential for the parasite's basic cellular survival, growth, and virulence. These prioritized proteins were identified to have appropriate binding pockets to anchor small drug-like compounds. Among these, UDPase and PCNA were prioritized as the top-ranked druggable proteins. The pharmacophore-based virtual screening and ADME profiling predicted MolPort-000-730-162 and MolPort-020-232-354 as the top hit drug-like compounds from the Pharmit resource to inhibit L. tropica UDPase and PCNA, respectively. The alternative drug targets and drug-like molecules predicted in the current study lay the groundwork for developing novel antileishmanial therapies.