Design, synthesis, crystal structure of novel hydrazone analogues as SARS-CoV-2 potent inhibitors: MD simulations, MM-GBSA, docking and ADMET studies

In this study, we have synthesized novel thiohydrazone <b>3(a-b)</b> and hydrazone analogues <b>3(c)</b> by one-pot methodology with good to excellent yields (85%-91%). <i>In silico</i> molecular dynamics (MD) simulations, docking, and absorption, distribution, metabolism, excretion and toxicity (ADMET) were evaluated as inhibitor activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PDB ID: 5N5O) main protease. The dynamics simulations studies and docking were conducted by GROMACS and AutoDock Vina. The ADMET studies of all the compounds were evaluated to understand drug-likeness and potential for therapeutic applications. All the synthesized compounds <b>3(a-c)</b> exhibited strong docking scores between -5.0 and -5.4 kcal mol^-1 to the targeted protein. MD simulations revealed that the <b>3b</b> protein-ligand complex demonstrated conformational stability throughout most of the 70 ns simulation period with root mean square deviation (RMSD) fluctuations below 3 Å. ADMET predictions indicated that all compounds possessed high gastrointestinal absorption, suggesting good oral bioavailability. By slow evaporation technique, crystals of compound <b>3b</b> were grown using ethanol and its single crystal X-ray diffraction analysis disclosed that it crystallized in the monoclinic (P2₁/c) crystal system. Crystal data outlined crystal packing, bond lengths, bond angles, intermolecular hydrogen bonding parameters, etc. This study offers further avenues in the discovery of novel and promising hydrazone analogues against SARS-CoV-2 main protease.