In-silico identification of novel natural drug leads against the Ebola virus VP40 protein: A promising approach for developing new antiviral therapeutics

Ebola, one of the deadliest known infectious diseases, was the root of epidemics in Western Africa from 2013 to 2016. Like other deadly viruses in the family Filoviridae with a high fatality rate, this virus also causes hemorrhagic fever. As a result, the Ebola virus (EBOV) represents a threat to global health. Since there are currently no effective treatments for EBOV infections, this study aims to identify potential natural drug candidates that may block the EBOV VP40 to prevent Ebola infections. The compounds were analyzed using ADMET, molecular docking, post-docking MM-GBSA, and molecular dynamics (MD) simulations. ADMET analysis identified 187 out of 452 compounds. According to molecular docking, the best three compounds were chosen from 187 compounds for further study with binding affinity −8.469, −8.175, and −7.918 kcal/mol for CID_21721878 (Kushenol L), CID_133561472 (2-[2,4-dihydroxy-5-[2-(2-hydroxypropan-2-yl)-5-methylphenyl]phenyl]-5,7-dihydroxy-2,3-dihydrochromen-4-one), and Amb_29844215 (Cathayanon I), respectively. The lead three compounds coordinated with the protein's shared amino acid residues (ILE216, PRO286, VAL287, LEU288, LEU213, PRO146, and VAL100) during molecular docking with hydrophobic bonds. Then, molecular docking results were validated using post-docking MM-GBSA of those three compounds are Kushenol L, 2-[2,4-dihydroxy-5-[2-(2-hydroxypropan-2-yl)-5-methylphenyl]phenyl]-5,7-dihydroxy-2,3-dihydrochromen-4-one and Cathayanon I had negative binding free energies of −69.53, −52.85, and −59.74 kcal/mol, respectively. All the selected compounds exhibit favorable pharmacokinetic (Pk) and toxicological properties, supporting their safety and efficacy. These three compounds were further evaluated using MD simulation, confirming the compounds' binding stability to the desired protein. After MD simulation, PCA, and DCCM analysis were performed. From all of these can suggest the best compound which is CID_21721878 (Kushenol L), which is a phytochemical derived from Cannabis sativa, another one is CID_13356472 which comes after Kushenol L, which is also a phytochemical found in several plants: Maclura tricuspidate, Euchresta japonica, Maclura pomifera. Both compounds can potentially inhibit EBOV VP40 protein activity