Computational Investigation of the Potential Antileishmanial Mechanism of the Nitroindazole Derivative VATR131

<b>Background:</b> Neglected tropical diseases (NTDs) significantly impact global health, particularly affecting impoverished communities. Among these diseases, leishmaniasis, caused by protozoan parasites of the genus <i>Leishmania</i> and transmitted through sandfly vectors, remains a challenge due to limited therapeutic options. Current treatments often suffer from significant limitations, such as high toxicity, limited efficacy, and the emergence of drug resistance. <b>Objectives:</b> This study investigates the potential antileishmanial mechanism of action of nitroindazole derivatives, specifically evaluating the compound VATR131, a molecule with notable selectivity and potency against <i>Leishmania infantum</i>. <b>Methods:</b> We employed computational methodologies, including target fishing, molecular docking, and atomistic molecular dynamics simulations, to identify and characterize potential molecular targets of VATR131. <b>Results:</b> The analysis revealed cysteine peptidase A as a promising target potentially mediating the antileishmanial activity of VATR131. Molecular dynamics simulations suggest critical hydrophobic interactions and hydrogen bonds between the compound and its most likely receptor, thus offering deeper insights into its potential mechanism of action. <b>Conclusions:</b> These findings contribute to the development of novel and effective therapies for leishmaniasis, highlighting the need for experimental validation and continued investigation of nitroindazole derivatives as promising therapeutic candidates.