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Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (m^pro): a molecular docking, molecular dynamics and structure-activity relationship studies.

ABSTRACT: SARS-COV-2, the novel coronavirus and root of global pandemic COVID-19 caused a severe health threat throughout the world. Lack of specific treatments raised an effort to find potential inhibitors for the viral proteins. The recently invented crystal structure of SARS-CoV-2 main protease (M^pro) and its key role in viral replication; non-resemblance to any human protease makes it a perfect target for inhibitor research. This article reports a computer-aided drug design (CADD) approach for the screening of 118 compounds with 16 distinct heterocyclic moieties in comparison with 5 natural products and 7 repurposed drugs. Molecular docking analysis against M^pro protein were performed finding isatin linked with a oxidiazoles (A2 and A4) derivatives to have the best docking scores of -11.22 kcal/mol and -11.15 kcal/mol respectively. Structure-activity relationship studies showed a good comparison with a known active M^pro inhibitor and repurposed drug ebselen with an IC₅₀ value of -0.67 μM. Molecular Dynamics (MD) simulations for 50 ns were performed for A2 and A4 supporting the stability of the two compounds within the binding pocket, largely at the S1, S2 and S4 domains with high binding energy suggesting their suitability as potential inhibitors of M^pro for SARS-CoV-2.

SUBMITTER: Badavath VN

PROVIDER: S-EPMC7682386 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (m<sup>pro</sup>): a molecular docking, molecular dynamics and structure-activity relationship studies.

Badavath Vishnu Nayak VN Kumar Akhil A Samanta Pralok K PK Maji Siddhartha S Das Anik A Blum Galia G Jha Anjali A Sen Anik A

Journal of biomolecular structure & dynamics 20201117 7

SARS-COV-2, the novel coronavirus and root of global pandemic COVID-19 caused a severe health threat throughout the world. Lack of specific treatments raised an effort to find potential inhibitors for the viral proteins. The recently invented crystal structure of SARS-CoV-2 main protease (M<sup>pro</sup>) and its key role in viral replication; non-resemblance to any human protease makes it a perfect target for inhibitor research. This article reports a computer-aided drug design (CADD) approach ...[more]

PMID: 33200681

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Project description:Since the outbreak of the COVID-19 (coronavirus disease 19) pandemic, researchers have been trying to investigate several active compounds found in plants that have the potential to inhibit the proliferation of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). The present study aimed to evaluate bioactive compounds found in plants using a molecular docking approach to inhibit the main protease (Mpro) and spike (S) glycoprotein of SARS-CoV-2. The evaluation was performed on the docking scores calculated using AutoDock Vina (AV) as a docking engine. A rule of five (Ro5) was calculated to determine whether a compound meets the criteria as an active drug orally in humans. The determination of the docking score was performed by selecting the best conformation of the protein-ligand complex that had the highest affinity (most negative Gibbs' free energy of binding/ΔG). As a comparison, nelfinavir (an antiretroviral drug), chloroquine, and hydroxychloroquine sulfate (antimalarial drugs recommended by the FDA as emergency drugs) were used. The results showed that hesperidin, nabiximols, pectolinarin, epigallocatechin gallate, and rhoifolin had better poses than nelfinavir, chloroquine, and hydroxychloroquine sulfate as spike glycoprotein inhibitors. Hesperidin, rhoifolin, pectolinarin, and nabiximols had about the same pose as nelfinavir but were better than chloroquine and hydroxychloroquine sulfate as Mpro inhibitors. This finding implied that several natural compounds of plants evaluated in this study showed better binding free energy compared to nelfinavir, chloroquine, and hydroxychloroquine sulfate, which so far are recommended in the treatment of COVID-19. From quantum chemical DFT calculations, the ascending order of chemical reactivity of selected compounds was pectolinarin > hesperidin > rhoifolin > morin > epigallocatechin gallate. All isolated compounds' C=O regions are preferable for an electrophilic attack, and O-H regions are suitable for a nucleophilic attack. Furthermore, Homo-Lumo and global descriptor values indicated a satisfactory remarkable profile for the selected compounds. As judged by the RO5 and previous study by others, the compounds kaempferol, herbacetin, eugenol, and 6-shogaol have good oral bioavailability, so they are also seen as promising candidates for the development of drugs to treat infections caused by SARS-CoV-2. The present study identified plant-based compounds that can be further investigated in vitro and in vivo as lead compounds against SARS-CoV-2.

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Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (m^pro): a molecular docking, molecular dynamics and structure-activity relationship studies.

Publications

Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (m<sup>pro</sup>): a molecular docking, molecular dynamics and structure-activity relationship studies.

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Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (mpro): a molecular docking, molecular dynamics and structure-activity relationship studies.

Publications

Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (m<sup>pro</sup>): a molecular docking, molecular dynamics and structure-activity relationship studies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (m^pro): a molecular docking, molecular dynamics and structure-activity relationship studies.