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Respiratory illness due to SARS-CoV-2 emerged in 2019 and has a significant morbidity and mortality rate. The main protease (Mpro) is mainly responsible for viral replications, which acts as a good drug target to inhibit SARS-CoV-2-related diseases. Chemical compounds obtained from various herbal plants are showing potent antiviral activity against numerous viral diseases. Initial screening was performed with the phytochemicals against Mpro using molecular docking. This result shows that there is a strong interaction exhibited between active sites (His-41 and Cys-145) of Mpro with chemical compounds. In addition, ADME prediction and Lipinski's rule of five (RO5) calculations demonstrated that the selected compounds have potential drug-like properties. Further, molecular dynamics (MD) simulations were performed to understand the stability and structural changes of protein–ligand complexes for the top five compounds. MM/PBSA studies strongly suggested that compounds, β-spinasterol, and asarinin form stable complexes with Mpro. The most significant hot spot residues such as Thr-25, Met-49, Cys-145, Met-165, and Gln-189 have strongly interacted with the selected chemical compounds. Our calculations suggest that asarinin is the best inhibitor to the Mpro, which supports these candidates and could be potent antiviral agent against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Imidazole (Im) and imidazolium (ImH+) cations play a vital role in the stability of biomolecules in an aqueous environment. The importance of water molecules in the interaction between ImH+ and aromatic amino acids (AAs) is unprecedented. Thus, we have used both quantum mechanical (QM) and molecular dynamics (MD) simulation approaches to understand the nature of interactions between AAs and ImH+ with water molecules. The microscopic studies of AA models and ImH+–water (ImH+Wn, where n = 0–4) clusters were calculated using the M05-2X/6-31+G** method. From DFT calculations, it is observed that the absence of water molecules in ImH+ favors the N–H⋯π interactions (i.e., T-shape) with AAs, whereas the microhydrated clusters of ImH+ prefer to stabilize the stacking conformation. The presence of water-mediated hydrogen bonding (H-bonding) interactions is highly favorable for the stacked confirmation of AAs–ImH+ complexes. This also directly influences the energetics of the cluster. The magnitude of the interaction strength between ImH+Wn and the selected AAs is in the order of Phe < Tyr ∼ Trp. The water-mediated H-bonding interactions act as the main driving force for the stability of π-stacking complexes. Both DFT and MD studies reveal that the ImH+ cation and water molecules play a vital role in the protein stability and also this can intuitively initiate the denaturation process. [ABSTRACT FROM AUTHOR]