SARS-CoV-2 Mpro inhibitors (Guangzhou Medical University)

This study focused on developing and evaluating new alkaloid derivatives as potential inhibitors of the SARS-CoV-2 main protease (M^pro). Five novel alkaloid derivatives were synthesized using standard organic techniques and characterized via infrared and NMR spectroscopy. Pharmacokinetic properties were assessed using Lipinski's Rule of Five and computational tools. Density Functional Theory calculations and molecular docking with AutoDock Vina were employed to analyse molecular properties and interactions with SARS-CoV-2 M^pro. Anti-aggregation and anticoagulant activities were evaluated using aggregometry and coagulation assays. The synthesized compounds exhibited favourable pharmacokinetic properties, including molecular weights below 500 and suitable polar surface areas for bioavailability. Molecular docking revealed strong binding affinities for M^pro, with binding energies ranging from -7.6 to -8.8 kcal/mol. Compounds 1 and 2 showed significant inhibition of platelet aggregation and anticoagulant activity, prolonging prothrombin and activated partial thromboplastin times at 50 μM concentration. Biological activity analysis indicated moderate to high activity as GPCR ligands and protease inhibitors. The synthesized alkaloid derivatives demonstrated high potential as SARS-CoV-2 M^pro inhibitors with additional anti-aggregation and anticoagulant properties. These findings suggest promise for further development as therapeutic agents against COVID-19, although further research is necessary to understand their mechanisms, safety, and clinical application prospects.

As severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) variants continue to emerge, there is an urgent need to develop more effective antiviral drugs capable of combating the COVID‐19 pandemic. The main protease (M pro ) of SARS‐CoV‐2 is an evolutionarily conserved drug discovery target. The present study mainly focused on chemoinformatics computational methods to investigate the efficacy of our newly designed trifluoromethyl‐1,3,4‐oxadiazole amide derivatives as SARS‐CoV‐2 M pro inhibitors. Drug‐likeness absorption, distribution, metabolism, excretion, and toxicity analysis, molecular docking simulation, density functional theory (DFT), and molecular dynamics simulation methods were included. A comprehensive drug‐likeness analysis was performed on the 14 newly designed compounds ( 1a – 1n ), and this series of small molecule inhibitors showed potential anti‐SARS‐CoV‐2 activity. In order to reveal the mechanism of drug interaction, these novel compounds were classified by structure, and molecular docking simulations were performed. The results showed good interactions and identified the key amino acid residue GLY‐143. Further DFT analysis using B3LYP‐D3BJ functional and 6‐311 + + G (d, p) basis set was performed to optimize the optimal configuration of the M pro inhibitors, and the infrared spectrum of the vibration frequency was analyzed to clearly understand the structure and stability of the drug. The electrostatic potential map was analyzed to predict the reactivity of functional groups and protein‐substrate interactions. The frontier molecular orbital analysis and density of states map showed the reactivity level and stability of the drug itself, among which 1i had the smallest energy gap difference (Δ Egap = 3.64 ev), showing good reactivity. The analysis of global reactivity descriptors such as electrophilic index (ω) and chemical potential (μ) also showed that our newly designed M pro inhibitors had stronger interactions. Molecular dynamics simulation further revealed the stable binding of the M pro inhibitors in a solvent environment. The binding free energy results calculated by Molecular Mechanics / Poisson Boltzmann Surface Area (MM/PBSA) all exceeded the Food and Drug Administration‐approved standard reference drug (Nirmatrelvir), and the free energy landscape and principal component analysis also further described the energy sites formed during the binding process between the drug molecule and the ligand‐protein and the changes in conformation. These new series of small molecule inhibitors studied in this work will provide the necessary theoretical basis for the synthesis and activity evaluation of novel SARS‐CoV‐2 M pro inhibitors.