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- SARS-CoV-2, the causative virus for COVID-19 has now super-mutated into the Omicron (Om) variant. On its spike (S) glycoprotein alone, more than 30 substitutions have been characterized with 15 within the receptor binding domain (RBD); It therefore calls to question the transmissibility and antibody escapability of Omicron. This study was setup to investigate the Omicron RBD’s interaction with ACE2 (host receptor) and a SARS-CoV-2 neutralizing monoclonal antibody (mAb). In-silico mutagenesis was used to generate the Om-RBD in complex with ACE2 or mAb from the wildtype. HDOCK server was used to redock and score the mAbs in Om-RBD bound state relative to the wildtype. Stability of interaction between all complexes were investigated using all-atom molecular dynamics (MD). Analyses of trajectories showed that Om-RBD has evolved into an efficient ACE2 binder, via pi-pi (Om-RBD-Y501/ACE2-Y41) and salt-bridge (Om-RBD-K493/ACE2-Y41) interactions. Conversely, in binding mAb, it has become less efficient (Center of mass distance of RBD from mAb complex, wildtype ≈ 30 Å, Omicron ≈ 41 Å). Disruption of Om-RBD/mAb complex resulted from loose interaction between Om-RBD and the light chain complementarity-determining region residues. Omicron is expected to be better transmissible and less efficiently interacting with neutralizing convalescent mAbs with consequences on transmissibility provided other mutations within the S protein similarly promote cell fusion and viral entry.
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- The high mutation rate of SARS-CoV-2 genomic RNA has made COVID-19 more difficult to eradicate using currently available interventions. Hence, newer pharmaceutical strategies must be developed, especially those generally complementary and alternative medicines. In the current study, stem bark of Bridelia ferruginea Benth is presented as plausible source of ethno-pharmaceuticals actionable against key SARS-CoV-2 life cycle-dependent enzymes based on in vitro inhibition studies, LC-ESI-MS characterization and molecular docking studies. Bridelia ferruginea stem bark extracted with 1 % HCL-acidified water, water, butanol, chloroform, ethyl-acetate, and petroleum ether and assayed for in vitro inhibition of SARS-COV-2-gp/human ACE2 interaction. The lowest and the highest IC50 value were recorded for ethyl-acetate (3.550 mg/L) and chloroform (413.4 mg/L) extracts respectively. When the ethyl-acetate extract was tested for SARS-COV-2 protease inhibition in vitro, papain-like protease (PL-pro, IC50=1.981 mg/L) presented as the better target in comparison to the main protease (3CL-pro, IC50=10.13 mg/L). LC/MS analysis identified corilagin and Gallocatechin-[4-O-7]-epigallocatechin as the active principles whilst molecular docking revealed the plausible poses of the compounds within the binding pockets of SARS-COV-2-glycoprotien receptor binding pocket, 3CL-pro and PL-pro. Taken together, these findings identified Bridelia ferruginea stem bark as a plausible source of anti-SARS-COV-2 phytochemicals and propose that corilagin may play important role in this activity.
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