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

Overview

Journal ACS Omega

Publisher American Chemical Society

Date 2025 Jan 20

PMID 39829523

Authors

Jessika de O Viana

Karen C Weber

Luiz E G da Cruz

Rhayane de O Santos

Gerd B Rocha

Alessandro K Jordao

Euzebio G Barbosa

Affiliations

Soon will be listed here.

Abstract

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 (PTR1) 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 PTR1 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 PTR1, indicating it as a new promising PTR1 inhibitor.

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