Targeting Leishmania infantum Mannosyl-oligosaccharide glucosidase with natural products: potential pH-dependent inhibition explored through computer-aided drug design

Visceral Leishmaniasis (VL) is a serious public health issue, documented in more than ninety countries, where an estimated 500,000 new cases emerge each year. Regardless of novel methodologies, advancements, and experimental interventions, therapeutic limitations, and drug resistance are still challenging. For this reason, based on previous research, we screened natural products (NP) from Nuclei of Bioassays, Ecophysiology, and Biosynthesis of Natural Products Database (NuBBEDB), Mexican Compound Database of Natural Products (BIOFACQUIM), and Peruvian Natural Products Database (PeruNPDB) databases, in addition to structural analogs of Miglitol and Acarbose, which have been suggested as treatments for VL and have shown encouraging action against parasite’s N-glycan biosynthesis. Using computer-aided drug design (CADD) approaches, the potential inhibitory effect of these NP candidates was evaluated by inhibiting the Mannosyl-oligosaccharide Glucosidase Protein (MOGS) from Leishmania infantum, an enzyme essential for the protein glycosylation process, at various pH to mimic the parasite’s changing environment. Also, computational analysis was used to evaluate the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profile, while molecular dynamic simulations were used to gather information on the interactions between these ligands and the protein target. Our findings indicated that Ocotillone and Subsessiline have potential antileishmanial effects at pH 5 and 7, respectively, due to their high binding affinity to MOGS and interactions in the active center. Furthermore, these compounds were non-toxic and had the potential to be administered orally. This research indicates the promising anti-leishmanial activity of Ocotillone and Subsessiline, suggesting further validation through in vitro and in vivo experiments.

Fil: Goyzueta Mamani, Luis Daniel. Universidad Católica de Santa María; Perú

Fil: Barazorda Ccahuana, Haruna Luz. Universidad Católica de Santa María; Perú

Fil: Candia Puma, Mayron Antonio. Universidad Católica de Santa María; Perú

Fil: Sobreira Galdino, Alexsandro. Universidade Federal São João Del-Rei; Brasil

Fil: Machado de Avila, Ricardo Andrez. Universidade Do Extremo Sul Catarinense; Brasil

Fil: Cordeiro Giunchetti , Rodolfo. Universidade Federal de Minas Gerais; Brasil

Fil: Medina Franco, José L.. Universidad Nacional Autónoma de México; México

Fil: Jacobsen, Monica Ofelia. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Patobiologia Veterinaria. - Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Patobiologia Veterinaria.; Argentina

Fil: Ferraz Coelho, Eduardo Antonio. Universidade Federal de Minas Gerais; Brasil

Fil: Chávez Fumagalli, Miguel Angel. Universidad Católica de Santa María; Perú