Presently, there are no approved drugs or vaccines to treat COVID-19, which has spread to over 200 countries and at the time of writing was responsible for over 650,000 deaths worldwide. Recent studies have shown that two human proteases, TMPRSS2 and cathepsin L, play a key role in host cell entry of SARS-CoV-2. Importantly, inhibitors of these proteases were shown to block SARS-CoV-2 infection. Here, we perform virtual screening of 14,011 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 and cathepsin L. Potential phytochemical inhibitors were filtered by comparing their docked binding energies with those of known inhibitors of TMPRSS2 and cathepsin L. Further, the ligand binding site residues and non-covalent interactions between protein and ligand were used as an additional filter to identify phytochemical inhibitors that either bind to or form interactions with residues important for the specificity of the target proteases. This led to the identification of 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. Further, we have performed molecular dynamics (MD) simulations to analyze the stability of the protein-ligand complexes for the three top inhibitors of TMPRSS2 namely, qingdainone, edgeworoside C and adlumidine, and of cathepsin L namely, ararobinol, (+)-oxoturkiyenine and 3α,17α-cinchophylline. Interestingly, several herbal sources of identified phytochemical inhibitors have antiviral or anti-inflammatory use in traditional medicine. Further in vitro and in vivo testing is needed before clinical trials of the promising phytochemical inhibitors identified here.

Isolated cluster systems can help to elucidate the molecular level description of water-mediated proton transfer. Protonation of neutral 4-aminobenzoic acid (4ABA) occurs at the acid ( O -protomer) and amine ( N -protomer) functionalities, yielding two distinct species with relative energies dependent on the degree of hydration. Here, we measured the rates of intramolecular proton transfer in 4ABAH ⁺ ·(H ₂ O) ₆ ions upon protomer-selective vibrational excitation of initially cold (6 K) cluster ions isolated in a cryogenic ion trap. Interconversion rates were observed on the microsecond time scale. These results quantify the kinetics of proton transfers in the context of a closed, finite system at well-defined internal energies and therefore provide experimental benchmarks for theoretical efforts that are being developed to treat relatively slow, highly cooperative solvent-mediated chemical processes.