Computational Identification of Shikimic Acid Derivatives as Potential SARS-CoV-2 Inhibitors: An In Silico Approach.

INTRODUCTION: The emergence of the COVID-19 virus has presented a serious threat to global health, with its high contagion and fatality rates. Despite considerable efforts, the search for effective antiviral drugs is still limited and requires the identification of new therapeutic leads using state-of-the-art computational methods. METHODS: Here, structure-activity relationship (SAR) analysis was used to design shikimic acidbased compounds as anti-SARS-CoV-2 agents. The compounds were docked using the Schrödinger suite and Discovery Studio to assess their binding interactions with the SARS-CoV-2 main protease. ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties were also evaluated in silico. The lead compound was subjected to molecular dynamics (MD) simulation (100 ns) to explore the dynamics of the protein-ligand interaction. RESULTS: The docking results from Schrodinger suite ranged from -4.8 to -6.8 kcal/mol, while T1 and T2 showed the most favourable CDOCKER interaction energies ranged from -7.7 to -8.8 kcal/mol. Key interactions involved critical amino acid residues such as SER46, MET49, HIE41, GLN189, ARG188, ASP187, MET165, HIE164, THR24, THR25, LEU27, ASN142, and GLY143. The docked pose of the co-crystal ligand confirmed the docking protocol (RMSD = 0.9875 Å). The Discovery Studio results were in good agreement with Schrodinger, and ADMET predictions suggested good drug-like properties. Moreover, the 100-ns MD simulation showed the T2-protein complex to be stable. DISCUSSION: The docking, ADMET, and MD simulation studies indicate that the designed shikimic acid derivatives have good binding affinity and drug-like properties, and are stable in the active site of the SARS-CoV-2 main protease. The results suggest T2 as a potential lead compound. CONCLUSION: In conclusion, the study suggests that the shikimic acid-derived T2 could be a potential SARS-CoV-2 inhibitor with strong in silico evidence. But additional in vitro and in vivo experiments are needed to confirm its efficacy.