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Hybrid drug-screening strategy identifies potential SARS-CoV-2 cell-entry inhibitors targeting human transmembrane serine protease.

ABSTRACT: The spread of coronavirus infectious disease (COVID-19) is associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has risked public health more than any other infectious disease. Researchers around the globe use multiple approaches to identify an effective approved drug (drug repurposing) that treats viral infections. Most of the drug repurposing approaches target spike protein or main protease. Here we use transmembrane serine protease 2 (TMPRSS2) as a target that can prevent the virus entry into the cell by interacting with the surface receptors. By hypothesizing that the TMPRSS2 binders may help prevent the virus entry into the cell, we performed a systematic drug screening over the current approved drug database. Furthermore, we screened the Enamine REAL fragments dataset against the TMPRSS2 and presented nine potential drug-like compounds that give us clues about which kinds of groups the pocket prefers to bind, aiding future structure-based drug design for COVID-19. Also, we employ molecular dynamics simulations, binding free energy calculations, and well-tempered metadynamics to validate the obtained candidate drug and fragment list. Our results suggested three potential FDA-approved drugs against human TMPRSS2 as a target. These findings may pave the way for more drugs to be exposed to TMPRSS2, and testing the efficacy of these drugs with biochemical experiments will help improve COVID-19 treatment.

Supplementary information

The online version contains supplementary material available at 10.1007/s11224-022-01960-w.

SUBMITTER: Feng Y

PROVIDER: S-EPMC9091140 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSARS-CoV-2 infection or COVID-19 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 because of the role it plays during the viral entry into the cell. Virtual screening of phytochemicals as potential inhibitors of TMPRSS2 can lead to the discovery of drug candidates for the treatment of COVID-19.PurposeThe study was designed to screen 132 phytochemicals from three medicinal plants traditionally used as antivirals; Zingiber officinalis Roscoe (Zingiberaceae), Artemisia annua L. (Asteraceae), and Moringa oleifera Lam. (Moringaceae), as potential inhibitors of TMPRSS2 for the purpose of finding therapeutic options to treat COVID-19.MethodsHomology model of TMPRSS2 was built using the ProMod3 3.1.1 program of the SWISS-MODEL. Binding affinities and interaction between compounds and TMPRSS2 model was examined using molecular docking and molecular dynamics simulation. The drug-likeness and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of potential inhibitors of TMPRSS2 were also assessed using admetSAR web tool.ResultsThree 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 TMPRSS2 inhibitor), which served as a control. All the three compounds exhibited good drug-like properties by not violating the Lipinski rule of 5. Niazirin and moringyne possessed good ADMET properties and were stable in their interactions with the TMPRSS2 based on the molecular dynamics simulation. However, the ADMET tool predicted the potential hepatotoxic and mutagenic effects of quercetin.ConclusionThis study demonstrated the potentials of niazirin, quercetin, and moringyne from M. oleifera, to inhibit the activities of human TMPRSS2, thus probably being good candidates for further development as new drugs for the treatment or management of COVID-19.

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Hybrid drug-screening strategy identifies potential SARS-CoV-2 cell-entry inhibitors targeting human transmembrane serine protease.

Supplementary information

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