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.

Instituto de Patobiología

Fil: Goyzueta-Mamani, Luis Daniel. Universidad Católica de Santa María. Vicerrectorado de Investigación. Computational Biology and Chemistry Research Group; Perú

Fil: Barazorda-Ccahuana, Haruna Luz. Universidad Católica de Santa María. Vicerrectorado de Investigación. Computational Biology and Chemistry Research Group; Perú

Fil: Candia-Puma, Mayron Antonio. Universidad Católica de Santa María. Vicerrectorado de Investigación. Computational Biology and Chemistry Research Group; Perú

Fil: Candia-Puma, Mayron Antonio. Universidad Católica de Santa María. Facultad de Ciencias Farmacéuticas, Bioquímicas y Biotecnológicas; Perú

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

Fil: Machado-de-Avila, Ricardo Andrez. Universidade do Extremo Sul Catarinense. Programa de Pós-Graduação em Ciências da Saúde; Brasil

Fil: Giunchetti, Rodolfo Cordeiro. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Laboratório de Biologia das Interações Celulares; Brasil

Fil: Giunchetti, Rodolfo Cordeiro. Instituto Nacional de Ciência e Tecnologia de Doenças Tropicais (INCT-DT); Brasil

Fil: Medina-Franco, José L. Universidad Nacional Autónoma de México. School of Chemistry. Department of Pharmacy. DIFACQUIM Research Group; México

Fil: Florin-Christensen, Mónica. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Patobiología Veterinaria; Argentina

Fil: Florin-Christensen, Mónica. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Fil: Ferraz Coelho, Eduardo Antonio. Universidade Federal de Minas Gerais. Faculdade de Medicina. Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical; Brasil

Fil: Ferraz Coelho, Eduardo Antonio. Universidade Federal de Minas Gerais. Colégio Técnico da Universidade Federal de Minas Gerais (COLTEC). Departamento de Patologia Clínica; Brasil

Fil: Chavez Fumagalli, Miguel Angel. Universidad Católica de Santa María. Vicerrectorado de Investigación. Computational Biology and Chemistry Research Group; Perú