Harnessing SuperNatural database to identify VP35 inhibitors as anti-Ebola drug candidates: A multistage <i>In silico</i> study

Ebola virus is a member of the <i>Filoviridae</i> family, which causes hemorrhagic fever in primates, exhibiting a mortality rate that can reach up to 90%. The VP35 suppresses the host IFN-<i>β/α</i> production by disrupting the immune responses of the host during viral infection, making it a putative target for therapeutic intervention. Herein, the UMH SuperNatural II database was mined to identify prospective VP35 inhibitors employing advanced <i>in</i> <i>silico</i> approaches. Filtration of the UMH SuperNatural II database was first conducted based on drug-likeness features. These compounds were screened towards VP35, and those exhibiting docking scores lower than 1DK, a reference ligand, further underwent molecular dynamics simulations (MDS), followed by binding energy calculations. Upon the assessed binding energy throughout 200 ns MDS, UMHSN00005544 and UMHSN00005545 disclosed superior binding affinity against VP35 compared to 1DK, with Δ<i>G</i>_binding values of -35.5, -34.9, and -29.3 kcal/mol, respectively. Energetic and structural evaluations were conducted for the identified natural compounds in complex with VP35 over 200 ns MDS. Post-MD analyses demonstrated the significant constancy of the investigated complexes. RMSD values averaged 0.14, 0.13, and 0.12 nm for UMHSN00005544, UMHSN00005545, and 1DK bound to VP35 over 200 ns MDS, indicating stable protein-ligand conformations. Furthermore, the ADMET characteristics of the identified natural compounds were assessed, revealing favorable pharmacokinetic and non-toxicity profiles. Density functional theory computations unveiled the electronic stability and chemical reactivity of the identified natural compounds. The obtained outcomes affirmed the substantial therapeutic potential of UMHSN00005544 and UMHSN00005545 as prospective candidates for combating EBOV, thereby necessitating further experimental investigations.