Despite the remarkable development of highly effective vaccines, including mRNA-based vaccines, within a limited timeframe, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not been entirely eradicated. Thus, it is crucial to identify new effective anti-3CLPro compounds, pivotal for the replication of SARS-CoV-2. Here, we identified an antcin-B phytosterol-like compound from Taiwanofungus camphoratus that targets 3CLPro activity. MTT assay and ADMET prediction are employed for assessing potential cytotoxicity. Computational molecular modeling was used to screen various antcins and non-antcins for binding affinity and interaction type with 3CLPro. Further, these compounds were subjected to study their inhibitory effects on 3CLPro activity in vitro. Our results indicate that antcin-B has the best binding affinity by contacting residues like Leu141, Asn142, Glu166, and His163 via hydrogen bond and salt bridge and significantly inhibits 3CLPro activity, surpassing the positive control compound (GC376). The 100 ns molecular dynamics simulation studies showed that antcin-B formed consistent, long-lasting water bridges with Glu166 for their inhibitory activity. In summary, antcin-B could be useful to develop therapeutically viable drugs to inhibit SARS-CoV-2 replication alone or in combination with medications specific to other SARS-CoV-2 viral targets.
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