Luteolin: a blocker of SARS-CoV-2 cell entry based on relaxed complex scheme, molecular dynamics simulation, and metadynamics.

Natural products have served human life as medications for centuries. During the outbreak of COVID-19, a number of naturally derived compounds and extracts have been tested or used as potential remedies against COVID-19. Tetradenia riparia extract is one of the plant extracts that have been deployed and claimed to manage and control COVID-19 by some communities in Tanzania and other African countries. The active compounds isolated from T. riparia are known to possess various biological properties including antimalarial and antiviral. However, the underlying mechanism of the active compounds against SARS-CoV-2 remains unknown. Results in the present work have been interpreted from the view point of computational methods including molecular dynamics, free energy methods, and metadynamics to establish the related mechanism of action. Among the constituents of T. riparia studied, luteolin inhibited viral cell entry and was thermodynamically stable. The title compound exhibit residence time and unbinding kinetics of 68.86 ms and 0.014 /ms, respectively. The findings suggest that luteolin could be potent blocker of SARS-CoV-2 cell entry. The study shades lights towards identification of bioactive constituents from T. riparia against COVID-19, and thus bioassay can be carried out to further validate such observations.

Ensemble-based screening of natural products and FDA-approved drugs identified potent inhibitors of SARS-CoV-2 that work with two distinct mechanisms.

The recent outbreak of SARS-CoV-2 is responsible for high morbidity and mortality rate across the globe. This requires an urgent identification of drugs and other interventions to overcome this pandemic. Computational drug repurposing represents an alternative approach to provide a more effective approach in search for COVID-19 drugs. Selected natural product known to have antiviral activities were screened, and based on their hits; a similarity search with FDA approved drugs was performed using computational methods. Obtained drugs from similarity search were assessed for their stability and inhibition against SARS-CoV-2 targets. Diosmin (DB08995) was found to be a promising drug that works with two distinct mechanisms, preventing viral replication and viral fusion into the host cell. Isoquercetin (DB12665) and rutin (DB01698) work by inhibiting viral replication and preventing cell entry, respectively. Our analysis based on molecular dynamics simulation and MM-PBSA binding free energy calculation suggests that diosmin, isoquercetin, rutin and other similar flavone glycosides could serve as SARS-CoV-2 inhibitor, hence an alternative solution to treat COVID-19 upon further clinical validation.