Molecular docking and dynamics of flexible heteroarotinoids as potential inhibitors against SARS-CoV-2 proteins .

The COVID-19 pandemic caused by the SARS-CoV-2 virus is a great threat to public health due to its high infection and mortality rates. In an effort to find a cure, researchers have been exploring different therapeutics that target the virus proteins with some success. Computational methods have been proven effective in studying biological macromolecule and drug discovery. This study utilizes an in-silico molecular docking approach to screen 26 anti-cancer compounds known as flexible heteroarotinoids against all 24 SARS-CoV-2 proteins. Out of 624 docked complexes analyzed, 69 showed binding energies between -9.0 to -11.6 kcal/mol, indicating good to strong binding affinities, with a binding constant K_D of 100 to 1 nmol. Based on the results, at least five compounds displayed excellent binding affinities against functionally significant proteins in the virus life cycle, such as non-structural protein 2, papain-like protease, non-structural protein 4, proof-reading exoribonuclease, membrane protein, and nucleocapsid protein. Analysis of the structure-activity relationships (SARs) showed that flexible heteroarotinoids with a urea linker instead of a thiourea linker, enhanced hydrophobic side chains in the chromane unit, and CF₃ or OCF₃ functional groups attached to the benzene ring exhibited better binding affinities. Further studies on the dynamics of the results are required to explore the potential of repurposing and developing a potent multi-target drug candidate to combat COVID-19.