IN SILICON EVALUATION OF ARTEMISININ DERIVATIVES AS POTENTIAL INHIBITORS OF SARS-COV-2 MAIN PROTEASE

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.

Natural Metabolites from Clinacanthus nutans as Promising SARS-CoV-2 Main Protease Inhibitors: Insights from Molecular Docking and Dynamics Simulations

Structure-based drug design against SARS-CoV-2 main protease (Mpro) was enabled by the availability of its crystal structure (PDB ID: 6LU7). In this study, metabolites from Clinacanthus nutans were computationally evaluated as potential Mpro inhibitors using validated molecular docking and molecular dynamics (MD) approaches. Native ligand re-docking produced an RMSD of 1.329 Å, confirming the reliability of the docking setup. Among the tested compounds, vitexin demonstrated a favorable binding affinity in docking analysis, indicating its potential for interaction within the active site of Mpro. However, further evaluation using 100 ns MD simulations and MM/PBSA free energy calculations revealed that, although the vitexin–Mpro complex remained relatively stable, the native ligand exhibited superior thermodynamic stability and binding free energy. Overall, vitexin shows promising binding characteristics as a natural compound targeting Mpro, but it does not surpass the native ligand in terms of overall binding stability. These findings suggest that vitexin may serve as a potential lead compound, warranting further optimization and experimental validation.

In silico Molecular Docking, Dynamics, and ADMET Analyses of Leritrelvir Targeting SARS-CoV-2 Main Protease

The current COVID19 pandemic necessitates the development of antiviral agents targeting the SARS-CoV-2 main protease. It is one of the viral enzymes that plays a key role in reproduction. Rayitrelvir (RAY1216), a 2-ketoamide-based peptidomimetic inhibitor, is presently in clinical development. To determine the nature and dynamics of Leritrelvir (RAY1216) binding to Mpro (PDB ID: 6LU7), structure-based molecular docking and dynamics simulation were used in this study to clarify the nature and dynamic stability of Leritrelvir (RAY1216). AutoDock was used to dock, and further validation was done on the DockThor platform. The interactive analysis showed that Leritrelvir (RAY1216) was highly stably bound in the catalytic pocket (7.3 kcal/mol), which was hydrogen bonded with GLN110, HIS246, GLU240, GLN110, and PRO108 and interacted π-π with HIS246 and PHE294. Docking comparative with Nirmatrelvir, the active compound of Paxlovid, showed a similar binding affinity (ΔG = -7.16 kcal/mol) and partially overlapping binding residues, which confirmed the reliability of docking results. Conformational stability of the LeritrelvirMpro complex was confirmed by a 100ns MD that showed stable RMSD, radius of gyration, and maintained hydrogen bonding, whereas the RMSF variations were localized to flexible terminal areas. ADMET predictions (SwissADME and ProTox-II) in silico revealed good pharmacokinetics and oral bioavailability, and good toxicity. When combined, these results provide docking, dynamics, and pharmacokinetics, making Leritrelvir (RAY1216) an effective noncovalent SARS-CoV2 Mpro inhibitor. However, additional in vitro and in vivo studies are justified to establish its potential in clinical use as a next-generation therapeutic to treat COVID19.

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

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.

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.