Identification of Promising Xanthene, Coumarin, and Benzoxazole Scaffolds against SARS-CoV-2 Proteases via In Silico Screening

Even though COVID-19 is no longer considered a pandemic, SARS-CoV-2 continues to evolve through frequent mutations, giving rise to new variants and maintaining its relevance as a global public health concern. The lack of effective, orally available antiviral treatments complicates clinical management, underscoring the need to develop broad-spectrum antiviral agents capable of addressing current and future viral outbreaks. In this study, a molecular docking approach was applied to evaluate the binding interactions of 118 marine-derived compounds and 92 previously synthesized compounds with the SARS-CoV-2 main protease and papain-like protease. Compounds belonging to the xanthene, benzoxazole, and coumarin families were identified as the most promising candidates. Overall, marine-origin compounds exhibited a marginally stronger inhibitory potential against the target enzymes. However, synthetic compounds demonstrated comparable binding performance, with leading molecules showing affinities of 0.2-0.4 mM. Among all evaluated structures, xanthenes—present in both marine and synthetic libraries—emerged as the most favorable scaffolds for further optimization as enzyme inhibitors. In addition, the papain-like protease appeared to be more amenable to drug targeting than the main protease. All top-ranked compounds also fulfilled standard drug-likeness criteria, suggesting suitable oral bioavailability and a low probability of adverse pharmacological effects. Collectively, these findings offer comparative insights into the binding behaviors of marine-derived and synthetic xanthene, coumarin, and benzoxazole derivatives and identify lead candidates for subsequent in vitro and in vivo experimental validation.