In Silico Structural Insights and Potential Inhibitor Identification Based on the Benzothiazole Core for Targeting Leishmania major Pteridine Reductase 1

Leishmaniasis is reported as the second most common protozoonosis, with the highest prevalence and mortality rate. Among the Leishmania drug targets, Pteridine Reductase 1 of Leishmania major (LmPTR1) proved to be promising because Leishmania is auxotrophic for folates. Thus, this study employed a combination of ligand- and structure-based approaches to screen new benzothiazole compounds as LmPTR1 inhibitor candidates. Initially, a highly predictive quantitative structure–activity relationship (QSAR) model was able to identify the relevant hybrid descriptors, with an accuracy of over 93%. Insights into the mechanism of action indicated Phe113, His241, Leu188, Met183, and Leu226 as key residues. New commercially available compounds were screened using QSAR, docking, and pharmacokinetic properties as filters. Molecular dynamics, non-covalent interactions analysis, and quantum chemical calculation of binding enthalpy demonstrated that the lead compound (ZINC 72229720) forms a stable complex with LmPTR1, indicating it as a new promising LmPTR1 inhibitor.