Targeting of Leishmania proteins by β-Lapachone derivatives reveals a promising multitarget candidate.

Leishmaniasis represents one of the major global public health problems. Canine leishmaniasis plays a significant role in perpetuating this condition, due to the limited therapeutic options available, which are costly, require prolonged treatment regimens, and are associated with the growing emergence of drug resistance. In this context, β-lapachone, a bioactive naphthoquinone derived from lapachol, has emerged as a potential therapeutic alternative due to its pharmacological properties, including antiparasitic activity, which characterizes it as a promising alternative for the development of new antileishmanial agents. In this study, a group of β-lapachone derivatives was evaluated using an integrated computational approach to investigate their antileishmanial potential and pharmacokinetic profile. Molecular docking simulations indicated greater selectivity of the compounds for Leishmania spp. targets compared to currently used drugs. Among the derivatives analyzed, compound LPI3 stood out as the lead compound, exhibiting a promising multitarget profile. Molecular dynamics analyses based on normal mode analysis revealed high conformational stability of the protein-ligand complexes involving LPI3, similar to that observed for the reference drugs. The physicochemical properties, as well as predictions of pharmacokinetic descriptors related to absorption, distribution, metabolism, excretion, and toxicity, indicated a favorable profile for the lead compound, consistent with drug-likeness and safety criteria. Therefore, the findings identified LPI3 as a potential candidate for future experimental evaluations in the treatment of leishmaniasis.