Gyaltsen Dakpa
Biography
Research Interest
Abstract
Natural Product?Based Inhibition of SARS-CoV-2 3CLpro by Antcin-B: Mechanistic and
Translational Insights
Despite the remarkable development of highly effective vaccines, including mRNA-based
formulations, against the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), complete eradication remains elusive. As viral proteins
like 3CLpro trigger an overactive immune response, it could lead to hyperinflammatory conditions
such as Multisystem Inflammatory Syndrome in Children (MIS-C). Hence, there is a pressing need
to uncover novel compounds capable of effectively targeting the 3CLpro enzyme crucial for
SARS-CoV-2 replication. This study identified an antcin-B phytosterol-like compound sourced
from Taiwanofungus camphoratus, which exhibits potent activity against 3CLPro. Through MTT
assay and ADMET prediction, we evaluated its potential cytotoxicity. We used computational
molecular modeling to screen various antcins and non-antcins for their binding affinity and
interaction patterns with 3CLPro. Subsequently, we examined the inhibitory effects of these
compounds on 3CLPro activity in vitro. Our findings reveal that antcin-B displays superior binding
affinity by establishing fundamental interactions with residues such as Leu141, Asn142, Glu166,
and His163 through hydrogen bonds and salt bridges. This results in significant inhibition of
3CLPro activity, surpassing that of the positive control compound (GC376). Molecular dynamics
simulations over 100 nanoseconds demonstrate that antcin-B forms stable, enduring water bridges
with Glu166, further elucidating its inhibitory mechanism. In summary, antcin-B emerges as a
promising candidate for developing therapeutically viable drugs to inhibit SARS-CoV-2
replication alone or with medications targeting other viral targets.
Keywords: Antcin-B, SARS-CoV-2, 3CLpro / Main Protease, Molecular Docking, Molecular
Dynamics Simulation, Natural Product Drug Discovery, Translational Medicine
