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Computational investigation of natural compounds as potential main protease (M^pro) inhibitors for SARS-CoV-2 virus.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is significantly impacting human lives, overburdening the healthcare system and weakening global economies. Plant-derived natural compounds are being largely tested for their efficacy against COVID-19 targets to combat SARS-CoV-2 infection. The SARS-CoV-2 Main protease (M^pro) is considered an appealing target because of its role in replication in host cells. We curated a set of 7809 natural compounds by combining the collections of five databases viz Dr Duke's Phytochemical and Ethnobotanical database, IMPPAT, PhytoHub, AromaDb and Zinc. We applied a rigorous computational approach to identify lead molecules from our curated compound set using docking, dynamic simulations, the free energy of binding and DFT calculations. Theaflavin and ginkgetin have emerged as better molecules with a similar inhibition profile in both SARS-CoV-2 and Omicron variants.

SUBMITTER: Patel CN

PROVIDER: S-EPMC9673090 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Computational investigation of natural compounds as potential main protease (M<sup>pro</sup>) inhibitors for SARS-CoV-2 virus.

Patel Chirag N CN Jani Siddhi P SP Prasanth Kumar Sivakumar S Modi Krunal M KM Kumar Yogesh Y

Computers in biology and medicine 20221118 Pt A

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is significantly impacting human lives, overburdening the healthcare system and weakening global economies. Plant-derived natural compounds are being largely tested for their efficacy against COVID-19 targets to combat SARS-CoV-2 infection. The SARS-CoV-2 Main protease (M<sup>pro</sup>) is considered an appealing target because of its role in replication in host cells. We curat ...[more]

PMID: 36423529

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Project description:In the past two years, the COVID-19 pandemic has caused over 5 million deaths and 250 million infections worldwide. Despite successful vaccination efforts and emergency approval of small molecule therapies, a diverse range of antivirals is still needed to combat the inevitable resistance that will arise from new SARS-CoV-2 variants. The main protease of SARS-CoV-2 (Mpro) is an attractive drug target due to the clinical success of protease inhibitors against other viruses, such as HIV and HCV. However, in order to combat resistance, various chemical scaffolds need to be identified that have the potential to be developed into potent inhibitors. To this end, we screened a high-content protease inhibitor library against Mproin vitro, in order to identify structurally diverse compounds that could be further developed into antiviral leads. Our high-content screening efforts retrieved 27 hits each with > 50% inhibition in our Mpro FRET assay. Of these, four of the top inhibitor compounds were chosen for follow-up due to their potency and drugability (Lipinski's rules of five criteria): anacardic acid, aloesin, aloeresin D, and TCID. Further analysis via dose response curves revealed IC50 values of 6.8 μM, 38.9 μM, 125.3 μM, and 138.0 μM for each compound, respectively. Molecular docking studies demonstrated that the four inhibitors bound at the catalytic active site of Mpro with varying binding energies (-7.5 to -5.6 kcal/mol). Furthermore, Mpro FRET assay kinetic studies demonstrated that Mpro catalysis is better represented by a sigmoidal Hill model than the standard Michaelis-Menten hyperbola, indicating substantial cooperativity of the active enzyme dimer. This result suggests that the dimerization interface could be an attractive target for allosteric inhibitors. In conclusion, we identified two closely-related natural product compounds from the Aloe plant (aloesin and aloeresin D) that may serve as novel scaffolds for Mpro inhibitor design and additionally confirmed the strongly cooperative kinetics of Mpro proteolysis. These results further advance our knowledge of structure-function relationships in Mpro and offer new molecular scaffolds for inhibitor design.

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Computational investigation of natural compounds as potential main protease (M^pro) inhibitors for SARS-CoV-2 virus.

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Computational investigation of natural compounds as potential main protease (M<sup>pro</sup>) inhibitors for SARS-CoV-2 virus.

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Computational investigation of natural compounds as potential main protease (Mpro) inhibitors for SARS-CoV-2 virus.

Publications

Computational investigation of natural compounds as potential main protease (M<sup>pro</sup>) inhibitors for SARS-CoV-2 virus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Computational investigation of natural compounds as potential main protease (M^pro) inhibitors for SARS-CoV-2 virus.