In silico identification of potential natural product inhibitors of human proteases key to SARS-CoV-2 infection

Abstract

Presently, there are no approved drugs or vaccines to treat COVID-19 which has spread to over 200 countries and is responsible for over 3,65,000 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 14010 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. We built a homology model of TMPRSS2 as an experimentally determined structure is not available. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 model structure and cathepsin L crystal structure. 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 protein-ligand interactions 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. We have identified 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. The top inhibitors of TMPRSS2 are Edgeworoside C, Adlumidine and Qingdainone, and of cathepsin L is Ararobinol. 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.