Computational screening of phytochemicals from three medicinal plants as inhibitors of the serine 2 transmembrane protease implicated in SARS-CoV-2 infection

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PhytomedPlus. 2021 Nov;1(4):100135. doi: 10.1016/j.phyplu.2021.100135. Published online September 29, 2021.


BACKGROUND: SARS-CoV-2 or COVID-19 infection is a major global public health issue that requires urgent attention in terms of drug development. Transmembrane protease serine 2 (TMPRSS2) is a good drug target against SARS-CoV-2 due to the role it plays during viral entry into the cell. Virtual screening of phytochemicals as potential TMPRSS2 inhibitors may lead to the discovery of drug candidates for the treatment of COVID-19.

OBJECTIVE: The study was designed to screen for 132 phytochemicals from three herbal medicines traditionally used as antivirals; Zingiber officinalis Roscoe (Zingiberaceae), Artemisia annual L. (Asteraceae), and Moringa oleifera lam. (Moringaceae), as potential inhibitors of TMPRSS2 with the aim of finding therapeutic options to treat COVID-19.

METHODS: The homology model of TMPRSS2 was constructed using the ProMod3 3.1.1 program from SWISS-MODEL. The binding affinities and the interaction between the compounds and the TMPRSS2 template were examined using molecular docking and molecular dynamics simulation. Drug-like and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of potential TMPRSS2 inhibitors were also assessed using the web-based admitSAR tool.

RESULTS: Three compounds, namely niazirin, quercetin and moringyne from M. oleifera demonstrated better molecular interactions with binding affinities ranging from -7.1 to -8.0 kcal/mol compared to -7.0 kcal/mol obtained for camostat mesylate (a known inhibitor of TMPRSS2), which served as a control. All three compounds exhibited good drug-like properties by not violating Lipinski’s rule of 5. Niazirin and moringyne exhibited good ADMET properties and were stable in their interactions with TMPRSS2 based on molecular dynamics simulation. However, the ADMET tool predicted the potential hepatotoxic and mutagenic effects of quercetin.

CONCLUSION: This study demonstrated the potentials of niazirin, quercetin and moringyne from M. oleiferato inhibit human TMPRSS2 activities, thus likely being good candidates for further development as novel drugs for the treatment or management of COVID-19.

PMID:35403085 | PMC:PMC8479425 | DOI:10.1016/j.phyplu.2021.100135

Alvin J. Chase