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Synthesis, molecular docking, and in silico ADME/Tox profiling studies of new 1-aryl-5-(3-azidopropyl)indol-4-ones: Potential inhibitors of SARS CoV-2 main protease.

ABSTRACT: The virus SARS CoV-2, which causes the respiratory infection COVID-19, continues its spread across the world and to date has caused more than a million deaths. Although COVID-19 vaccine development appears to be progressing rapidly, scientists continue the search for different therapeutic options to treat this new illness. In this work, we synthesized five new 1-aryl-5-(3-azidopropyl)indol-4-ones and showed them to be potential inhibitors of the SARS CoV-2 main protease (3CLpro). The compounds were obtained in good overall yields and molecular docking indicated favorable binding with 3CLpro. In silico ADME/Tox profile of the new compounds were calculated using the SwissADME and pkCSM-pharmacokinetics web tools, and indicated adequate values of absorption, distribution and excretion, features related to bioavailability. Moreover, low values of toxicity were indicated for these compounds. And drug-likeness levels of the compounds were also predicted according to the Lipinski and Veber rules.

SUBMITTER: Dominguez-Villa FX

PROVIDER: S-EPMC7683933 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Synthesis, molecular docking, and in silico ADME/Tox profiling studies of new 1-aryl-5-(3-azidopropyl)indol-4-ones: Potential inhibitors of SARS CoV-2 main protease.

Domínguez-Villa Francisco Xavier FX Durán-Iturbide Noemi Angeles NA Ávila-Zárraga José Gustavo JG

Bioorganic chemistry 20201124

The virus SARS CoV-2, which causes the respiratory infection COVID-19, continues its spread across the world and to date has caused more than a million deaths. Although COVID-19 vaccine development appears to be progressing rapidly, scientists continue the search for different therapeutic options to treat this new illness. In this work, we synthesized five new 1-aryl-5-(3-azidopropyl)indol-4-ones and showed them to be potential inhibitors of the SARS CoV-2 main protease (3CLpro). The compounds w ...[more]

PMID: 33261847

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Project description:SARS-CoV-2 is the foremost culprit of the novel coronavirus disease 2019 (nCoV-19 and/or simply COVID-19) and poses a threat to the continued life of humans on the planet and create pandemic issue globally. The 3-chymotrypsin-like protease (MPRO or 3CLPRO) is the crucial protease enzyme of SARS-CoV-2, which directly involves the processing and release of translated non-structural proteins (nsps), and therefore involves the development of virus pathogenesis along with outbreak the forecasting of COVID-19 symptoms. Moreover, SARS-CoV-2 infections can be inhibited by plant-derived chemicals like amentoflavone derivatives, which could be used to develop an anti-COVID-19 drug. Our research study is designed to conduct an in silico analysis on derivatives of amentoflavone (isoginkgetin, putraflavone, 4''''''-methylamentoflavone, bilobetin, ginkgetin, sotetsuflavone, sequoiaflavone, heveaflavone, kayaflavone, and sciadopitysin) for targeting the non-structural protein of SARS-CoV-2, and subsequently further validate to confirm their antiviral ability. To conduct all the in silico experiments with the derivatives of amentoflavone against the MPRO protein, both computerized tools and online servers were applied; notably the software used is UCSF Chimera (version 1.14), PyRx, PyMoL, BIOVIA Discovery Studio tool (version 4.5), YASARA (dynamics simulator), and Cytoscape. Besides, as part of the online tools, the SwissDME and pKCSM were employed. The research study was proposed to implement molecular docking investigations utilizing compounds that were found to be effective against the viral primary protease (MPRO). MPRO protein interacted strongly with 10 amentoflavone derivatives. Every time, amentoflavone compounds outperformed the FDA-approved antiviral medicine that is currently underused in COVID-19 in terms of binding affinity (- 8.9, - 9.4, - 9.7, - 9.1, - 9.3, - 9.0, - 9.7, - 9.3, - 8.8, and - 9.0 kcal/mol, respectively). The best-selected derivatives of amentoflavone also possessed potential results in 100 ns molecular dynamic simulation (MDS) validation. It is conceivable that based on our in silico research these selected amentoflavone derivatives more precisely 4''''''-methylamentoflavone, ginkgetin, and sequoiaflavone have potential for serving as promising lead drugs against SARS-CoV-2 infection. In consequence, it is recommended that additional in vitro as well as in vivo research studies have to be conducted to support the conclusions of this current research study.

Dataset Information

Synthesis, molecular docking, and in silico ADME/Tox profiling studies of new 1-aryl-5-(3-azidopropyl)indol-4-ones: Potential inhibitors of SARS CoV-2 main protease.

Publications

Synthesis, molecular docking, and in silico ADME/Tox profiling studies of new 1-aryl-5-(3-azidopropyl)indol-4-ones: Potential inhibitors of SARS CoV-2 main protease.

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