Identification and 3D Modeling of Novel Drug Targets in Leishmania Major: An in-silico Approach.

INTRODUCTION: Leishmania sp. can cause visceral, mucosal, cutaneous, and subcutaneous forms. Leishmania major is responsible for the cutaneous manifestation of the disease. Due to the limited treatment options and growing resistance in the disease, an in-silico study was conducted to find new therapeutic targets in L. major. METHODS: The choke point reactions present in the LeishCyc database were utilized to identify the enzymes responsible for catalyzing these reactions, to discover novel therapeutic targets. The sub-tractive genome approach was used to compare these enzymes with the human proteome to avoid off-target effects. The subcellular location of these enzymes was additionally predicted using DeepLock 2.0. Afterwards, protein-protein interactions were analyzed with STRINGv12.0, identifying high-confidence enzymes with highly ranked clusters. Their pathways and significance in parasite survival were determined via the Kyoto Encyclopedia of Genes and Genomes and relevant literature. Afterwards, the uniqueness of pharmacological targets and the potential for broad-spectrum activity of relevant enzymes were assessed using the DrugBank database and BLASTp analysis. Additionally, 3D structures were modeled and validated using SWISS MODEL and SAVESv6.0. RESULTS: The study proposed that Putative lanosterol 14-alpha demethylase, DPMS, and ADS1 have the potential to be effective therapeutic targets due to their innovative nature. An extensive investigation using BLASTp revealed that these selected pharmacological targets exhibit more than 90% similarity with other Leishmania species, suggesting their potential for therapeutic targeting throughout the Leishmania genus. CONCLUSION: The prospective pharmacological targets revealed in this work, specifically the putative lanosterol 14-alpha demethylase, DPMS, and ADS1, show promise for future investigation as potential therapeutic targets. Nevertheless, further in-vitro and in-vivo investigations are required to fully examine their complete therapeutic capabilities.