<i>In Silico</i> Structural Insights and\nPotential Inhibitor Identification Based on the Benzothiazole Core\nfor Targeting Leishmania major Pteridine\nReductase 1

Leishmaniasis is\nreported as the second most common protozoonosis,\nwith the highest prevalence and mortality rate. Among the Leishmania\ndrug targets, Pteridine Reductase 1 of Leishmania major (<i>Lm</i>PTR1) proved to be promising because Leishmania\nis auxotrophic for folates. Thus, this study employed a combination\nof ligand- and structure-based approaches to screen new benzothiazole\ncompounds as <i>Lm</i>PTR1 inhibitor candidates. Initially,\na highly predictive quantitative structure–activity relationship\n(QSAR) model was able to identify the relevant hybrid descriptors,\nwith an accuracy of over 93%. Insights into the mechanism of action\nindicated Phe113, His241, Leu188, Met183, and Leu226 as key residues.\nNew commercially available compounds were screened using QSAR, docking,\nand pharmacokinetic properties as filters. Molecular dynamics, non-covalent\ninteractions analysis, and quantum chemical calculation of binding\nenthalpy demonstrated that the lead compound (ZINC 72229720) forms\na stable complex with <i>Lm</i>PTR1, indicating it as a\nnew promising <i>Lm</i>PTR1 inhibitor.