In Silico Identification of Potent SARS-CoV-2 RdRp Inhibitors: DFT and Molecular Docking Analysis of Acylated Glucopyranoside Derivatives

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.

Identifying and Evaluating Flavonoids as Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro/3CL) Through Docking and Molecular Dynamics

Findings highlight glycosylated flavonoids as promising scaffolds for future structure-based optimization and provide structural insights to guide experimental validation.

Identification of potential SARS-CoV-2 Mpro inhibitors from a Thai natural product database via interaction fingerprint-based virtual screening

Fragment-based discovery of novel Baicalein derivatives as triple-target 3CLpro/PLpro/RdRp inhibitors against SARS-CoV-2.

The rapid evolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the emergence of drug resistance necessitate the development of multi-target antiviral therapeutics. This study aimed to computationally design a novel triple-target inhibitor derived from the natural flavonoid Baicalein, targeting the essential SARS-CoV-2 enzymes 3CLpro, PLpro, and RdRp to combat viral resistance. An integrated computational approach was employed, including virtual screening of compound libraries, molecular docking using Molecular Operating Environment software, fragment-based drug design to optimize Baicalein, and molecular dynamics simulations over 200 ns with AMBER 18 to assess binding stability. Binding free energies were calculated via MM/GBSA methods, and pharmacokinetic properties were evaluated using ADME/T predictions. Retrosynthetic analysis was performed to confirm synthetic feasibility. The novel compound BD02 demonstrated stable binding to all three targets, with significantly improved binding free energies compared to Baicalein: 3CLpro (-50.68 kcal/mol), PLpro (-59.05 kcal/mol), and RdRp (-51.98 kcal/mol). Molecular dynamics simulations showed low root mean square deviation values, indicating high structural stability. ADME/T predictions revealed favorable drug-like properties, including good absorption and low toxicity risks. BD02 is a computationally promising synthetic lead scaffold for broad-spectrum anti-coronavirus design. This multi-target design theoretically helps mitigate viral resistance and provides structural design references.

Identification of Potential SARS-CoV-2 Main Protease (MPro) Inhibitors Through Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Simulation Approaches

The findings suggest that Lig-1, followed by Lig-3, may serve as promising computational lead compounds targeting SARS-CoV-2 MPro, representing promising candidates for further experimental validation.

Marine Pyrrole Imidazole Alkaloids as Anti-Cathepsins Agents for SARS-CoV-2 Entry Inhibition: Insights from in silico Docking and Molecular Dynamic Simulations

An integrated computer-aided drug discovery approach for a selection of 14 pyrrole-imidazole alkaloids targeting Cathepsins L and B confirmed the structural stability of both the Cathepsin L-Mauritiamine and Cathepsin B-Mauritiamine complexes and underscore the potential of Mauritiamine as a promising candidate for antiviral therapy against SARS-CoV-2.