Computational studies of biomolecules to explore potential therapeutics for COVID-19 and SAMD9- associated diseases

The COVID-19 pandemic phase caused by the SARS-CoV-2 virus is over. However, emergence of new variants continues to threaten public health. Various therapeutics that target proteins of the virus have been studied, which have shown some degree of success. Advancements in computational methods have offered an excellent opportunity to explore biological macromolecule conformations, functions, and pathogenesis. Therefore, an in silico molecular docking and dynamics approach were used to search for interactions of 26 flexible heteroarotinoids, which are a class of anti-cancer compounds, as potential inhibitors against all 24 SARS-CoV-2 proteins. Of the 624 docked complexes, 69 displayed binding energies between –9.0 to –11.6 kcal/mol, indicating good to strong binding affinities with a binding constant Kᴰ of 100 to 1 nmol. Based on the docking results, at least 5 of these compounds displayed excellent binding affinities against non-structural protein 2, papain-like protease, non-structural protein 4, proof-reading exoribonuclease, membrane protein, and nucleocapsid protein. These proteins are functionally significant in the virus life cycle, making them prospective molecular targets for therapeutics. Structure–activity relationships (SARs) analysis of these results revealed that a urea linker in place of a thiourea linker, enhanced hydrophobic side chains attached to the chromane unit, and a CF₃ or OCF₃ functional group attached to the benzene ring contribute to increased binding affinities. Further, molecular dynamics simulation showed that complexes of compound FHT18-6c with non-structural protein 4 and nucleocapsid protein remained stable for at least 200 ns, leading to decreased structural fluctuations and increased compactness of the binding site. Additionally, computational docking analysis was carried out for the C-terminal dimerization domain of SARS-CoV-2 nucleocapsid protein and SHetA2, the parent compound of flexible heteroarotinoids. The functionally important residues involved in the docking interactions aligned with the results obtained using ¹⁵N-HSQC NMR titration experiment, which supports the computational results. Therefore, these top hits deserve further studies to explore the potential of repurposing and developing a potent multi-target drug candidate to combat COVID-19. SAMD9 acts as an antiviral and antiproliferative factor. However, mutations in SAMD9 are responsible for several diseases like MIRAGE syndrome, bone marrow failure, and immunodeficiency. Molecular modeling, docking, and dynamics simulation studies were carried out for the SAMD9 effector domain to study its interaction with double-stranded nucleic acid and salvianolic acid B for possible therapeutic strategies.