Avaliação in silico do potencial inibitório de terpenos de Ricinus communis L. sobre a MPro de SARS-CoV-2

Abstract

The SARS-CoV-2 virus, which causes COVID-19, is responsible for a highly contagious disease that can result in severe symptoms in humans. Various strategies have been proposed to combat COVID-19, with one promising approach being the inhibition of the main protease known as MPro (3CLpro). This protease plays a crucial role in viral replication and is both highly conserved and specific among coronaviruses, making it a key target for developing effective inhibitors. Ricinus communis L., commonly known as the castor bean plant, is an oil-rich species that belongs to the Euphorbiaceae family. It has diverse applications in both medical and industrial fields, highlighting its significant socioeconomic value in Brazil. To explore bioactive compounds derived from Brazil's native biodiversity for potential COVID-19 treatments, this study investigated the interactions between 34 terpenes from R. communis and MPro using an in silico methodology that combines Docking and Molecular Dynamics (MD) simulations. Docking analyses were conducted at the active site of MPro and were validated through redocking, cross-docking, correlations with biological activity, and decoys. These analyses were performed using software tools such as AutoDock 4.2, AutoDock Vina, DockThor, and GOLD, utilizing scoring functions like PLP, Goldscore, Chemscore, and ASP to elucidate the primary interactions between the R. communis terpenes and MPro. Based on the Lipinski Rule (Ro5) and efficiency metrics (LE, LLE, and FQ) calculated for each terpene, the five highest-ranked compounds- camphor, 1,8-cineole, α-thujone, ficusic acid, and 6α-hydroxy-10β-methoxy-7α,8α-epoxy-5-oxocasban-20-10-olide- were selected for subsequent MD studies. Following MD analyses, it was determined that among the selected terpenes, ficusic acid (LLE = 3.54, molecular mass = 196 g/mol, RMSD = 3.50 Å) and 6α-hydroxy-10β-methoxy-7α,8α-epoxy-5-oxocasban-20-10-olide (LLE = 3.50, molecular mass = 376 g/mol, RMSD = 9.94 Å) demonstrated noteworthy inhibitory potential against SARS-CoV-2 MPro. Notably, the interactions of these compounds with MPro have not been reported in the literature before, emphasizing their novelty. These findings highlight ficusic acid and 6α-hydroxy-10β-methoxy-7α,8α-epoxy-5-oxocasban-20-10-olide as promising candidates for future in vitro and in vivo studies aimed to treat COVID-19.