A computer simulation-based study on the intervention of active ingredients of Mongolian medicine into the S-protein of SARS-CoV-2-associated variant Omicron

Abstract BACKGROUND: Omicron VOC (BF.7) is a variant of SARS-CoV-2 that is currently spreading globally as a dominant strain. BF.7 is more infectious than existing Omicron variants, and to date there are no specific therapeutic agents for this variant. METHODS: The active compounds were collected by TCMSP, ETCM database and literature mining method, and the targets of the compounds were searched by Swiss Target Prediction and SUPERPRED database, while the targets of Omiron virus were collected by DisGeNET and GEO database, and then the intersecting targets were compared and analyzed. In this study, Swiss-Model was applied to construct the Spike RBD structure of Omicron variant BF.7 by replacing mutant amino acids into the Native Spike (S) structure, and the structural changes of Native S were compared. The four active compounds screened were docked with Omicron S protein and Omicron S-hACE2 complexes. To evaluate the structural stability of the complexes in a physiological environment, we also performed molecular dynamics simulations of the docked complexes and compared them to the control drug, chloroquine. The affinity of ligands and protein complexes was determined by free energy analysis using the MM-PBSA algorithm, and the structural changes of S proteins in combination with ligands were evaluated. RESULTS: A total of 12 mongolic medicines were screened and 310 active ingredient predictions were made, with a total of 55 genes overlapping with Omicron variants and 14 targets with the largest differences being conserved. Once these 14 targets were mapped to the active ingredients of 12 mongolic herbs, four more precise active ingredients were filtered out. Of these four phytochemicals, Berberine was the most potent inhibitor of Omicron S protein. In addition, molecular docking simulations revealed that Berberine can bind stably to Omicron S protein and the Omicron S-hACE2 complex. Using molecular dynamics simulations, Berberine was shown to be able to form a stable complex with Omicron S in a physiological environment with better results than the control drug chloroquine. Free energy analysis by the MM-PBSA algorithm and evaluation of S protein structural changes following ligand binding also demonstrated a higher affinity of Berberine for Omicron S compared to the other small molecule compounds. CONCLUSION: Berberine was found to have the most substantial inhibitory potential against Omicron VOC (BF.7) S protein and could be further investigated and developed as a potential inhibitor of Omicron.