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Virtual Screening of Transmembrane Serine Protease Inhibitors.

ABSTRACT: The human family of type II transmembrane serine proteases includes 17 members. The defining features of these proteases are an N-terminal transmembrane domain and a C-terminal serine protease of the chymotrypsin (S1) fold, separated from each other by a variable stem region. Recently accumulated evidence suggests a critical role for these proteases in development of cancer and metastatic capacity. Both the cancer relevance and the accessibility of the extracellularly oriented catalytic domain for therapeutic and imaging agents have fueled drug discovery interest in the type II class of transmembrane serine proteases. Typically, the initial hit discovery processes aim to identify molecules with verifiable activity at the drug target and with sufficient drug-like characters. We present here protocols for structure-based virtual screening of candidate ligands for transmembrane serine protease hepsin. The methods describe use of the 3D structure of the catalytic site of hepsin for molecular docking with ZINC, which is a molecular database of > 30 million purchasable compounds. Small candidate subsets were experimentally tested with demonstrable hits, which provided meaningful cues of the ligand structures for further lead development.

SUBMITTER: Poso A

PROVIDER: S-EPMC8410343 | 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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Virtual Screening of Transmembrane Serine Protease Inhibitors.

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