Let’s Not Neglect Drug Discovery to Combat COVID-19: In Silico Study of the Anti-Cancer Compounds Flexible Heteroarotinoids as Candidate Inhibitors Against SARS-CoV-2 Proteins

Abstract

The COVID-19 pandemic phase caused by the SARS-CoV-2 has ended, but the emergence of new variants continues to threaten public health. The public health toolbox for COVID-19 is in need of not only vaccines but also drug discovery against the SARS-CoV-2 virus, the causative agent for the ongoing COVID-19 infections. We report here an in silico molecular docking and dynamics study that uncovered the interactions of 26 flexible heteroarotinoids (FHT18), 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 and −11.6 kcal/mol, indicating good to strong binding affinities. At least five of these compounds displayed excellent binding affinities against the nonstructural protein 2, papain-like protease, nonstructural protein 4 (Nsp4), proof-reading exoribonuclease, membrane protein, and nucleocapsid protein. Structure–activity relationship (SAR) analyses of these results revealed that a urea linker in place of a thiourea linker, enhanced the hydrophobic side chains attached to the chromane unit, and a CF₃ or OCF₃ functional group attached to the benzene ring contributed to increased binding affinities. Further, the molecular dynamics simulation study of the best-docked complex FHT18-6c with Nsp4 remained stable for at least 200 ns, leading to decreased structural fluctuations and increased compactness of the binding site. In conclusion, FHT18-6c deserves further translational research to explore its potential for repurposing as a potent drug candidate to combat COVID-19. We also call for continued drug discovery efforts to enrich the public health toolbox for COVID-19.