Abstract
The coronavirus disease 2019 (COVID-19) has spread worldwide with severe health, social, and economic repercussions. Although vaccines have significantly reduced the severity of symptoms and deaths, alternative medications derived from natural products (NPs) are vital to further decrease fatalities, especially in regions with low vaccine uptake. When paired with the latest computational developments, NPs, which have been used to cure illnesses and infections for thousands of years, constitute a renewed resource for drug discovery. In the present report, a combination of computational and in vitro methods reveals the repositioning of NPs and identifies salvinorin A and deacetylgedunin (DCG) as having potential anti-SARS-CoV-2 activities. Salvinorin A was found both in silico and in vitro to inhibit both SARS-CoV-2 spike/host ACE2 protein interactions, consistent with blocking viral cell entry, and well as live virus replication. Plant extracts from Azadirachta indica and Cedrela odorata, which contain high levels of DCG, inhibited viral cell replication by targeting the main protease (Mpro) and/or inhibited viral cell entry by blocking the interaction between spike RBD-ACE2 protein at concentrations lower than salvinorin A. Our findings suggest that salvinorin A represent promising chemical starting points where further optimization may result in effective natural product-derived and potent anti-SARS-CoV-2 inhibitors to supplement vaccine efforts.