Cheminformatics approach to identify andrographolide derivatives as dual inhibitors of methyltransferases (nsp14 and nsp16) of SARS-CoV-2

Thomas et al., Scientific Reports, doi:10.1038/s41598-024-58532-7

Apr 2024

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In Silico study showing that andrographolide derivatives (PubChem CID 2734589 and 138968421) are potential dual inhibitors of SARS-CoV-2 methyltransferases nsp14 and nsp16, which are crucial for viral replication and evading host immune responses. Authors conducted virtual screening, molecular docking, ADMET profiling, molecular dynamics simulations, free-energy landscape analysis, and density functional theory calculations on 413 andrographolide derivatives. The two lead compounds formed stable complexes with nsp14 and nsp16 proteins via hydrophobic interactions, hydrogen bonds and electrostatic interactions, and had predicted class four toxicity with LD50 values of 500-700 mg/kg. Molecular dynamics simulations and binding free energy calculations confirmed the stability of the protein-ligand complexes.

24 preclinical studies support the efficacy of andrographolide for COVID-19:

12 In Silico studies1-12

9 In Vitro studies1,13-20

3 In Vivo animal studies13,17,20

In Vitro studies demonstrate inhibition of the M^proA,17 protein. In Vitro studies demonstrate efficacy in Calu-3B,17, A549C,13, and HUVECD,17 cells. Animal studies demonstrate efficacy in Sprague Dawley miceE,17 and Golden Syrian hamstersF,13. Andrographolide inhibits M^pro in a dose-dependent manner17, reduces ACE2 levels in the lung tissue of mice in combination with baicalein17, inhibits binding between the SARS-CoV-2 spike protein and ACE217, alleviates lung inflammation and cytokine storm in mice17, and improves survival and reduces lung inflammation via anti-inflammatory effects in Syrian hamsters13.

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1. Zhang et al., Effects and Mechanisms of Andrographolide for COVID-19: A Network Pharmacology-Based and Experimentally Validated Study, Natural Product Communications, doi:10.1177/1934578X241288428.sagepub.com, doi.org.

2. Thomas et al., Cheminformatics approach to identify andrographolide derivatives as dual inhibitors of methyltransferases (nsp14 and nsp16) of SARS-CoV-2, Scientific Reports, doi:10.1038/s41598-024-58532-7.nature.com, doi.org.

3. Bhattarai et al., Investigating the binding affinity of andrographolide against human SARS-CoV-2 spike receptor-binding domain through docking and molecular dynamics simulations, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2023.2174596.tandfonline.com, doi.org.

4. Nguyen et al., The Potential of Ameliorating COVID-19 and Sequelae From Andrographis paniculata via Bioinformatics, Bioinformatics and Biology Insights, doi:10.1177/11779322221149622.sagepub.com, doi.org.

5. Dassanayake et al., Molecular Docking and In-Silico Analysis of Natural Biomolecules against Dengue, Ebola, Zika, SARS-CoV-2 Variants of Concern and Monkeypox Virus, International Journal of Molecular Sciences, doi:10.3390/ijms231911131.mdpi.com, doi.org.

6. Ningrum et al., Potency Of Andrographolide, L-Mimosine And Asiaticoside Compound As Antiviral For Covid-19 Based On In Silico Method, Proceedings Universitas Muhammadiyah Yogyakarta Undergraduate Conference, doi:10.18196/umygrace.v2i2.418.ac.id, doi.org.

7. Ravichandran et al., Identification of Potential Semisynthetic Andrographolide Derivatives to Combat COVID-19 by Targeting the SARS-COV-2 Spike Protein and Human ACE2 Receptor– An In-silico Approach, Biointerface Research in Applied Chemistry, doi:10.33263/BRIAC132.155.biointerfaceresearch.com, doi.org.

8. Saeheng et al., In Silico Prediction of Andrographolide Dosage Regimens for COVID-19 Treatment, The American Journal of Chinese Medicine, doi:10.1142/S0192415X22500732.worldscientific.com, doi.org.

9. Khanal et al., Combination of system biology to probe the anti-viral activity of andrographolide and its derivative against COVID-19, RSC Advances, doi:10.1039/D0RA10529E.rsc.org, doi.org.

10. Rehan et al., A Computational Approach Identified Andrographolide as a Potential Drug for Suppressing COVID-19-Induced Cytokine Storm, Frontiers in Immunology, doi:10.3389/fimmu.2021.648250.frontiersin.org, doi.org.

11. Rajagopal et al., Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in silico approach, Future Journal of Pharmaceutical Sciences, doi:10.1186/s43094-020-00126-x.springeropen.com, doi.org.

12. Dey et al., The role of andrographolide and its derivative in COVID-19 associated proteins and immune system, Research Square, doi:10.21203/rs.3.rs-35800/v1.researchsquare.com, doi.org.

13. Kongsomros et al., In vivo evaluation of Andrographis paniculata and Boesenbergia rotunda extract activity against SARS-CoV-2 Delta variant in Golden Syrian hamsters: Potential herbal alternative for COVID-19 treatment, Journal of Traditional and Complementary Medicine, doi:10.1016/j.jtcme.2024.05.004.sciencedirect.com, doi.org.

14. Chaopreecha et al., Andrographolide attenuates SARS-CoV-2 infection via an up-regulation of glutamate-cysteine ligase catalytic subunit (GCLC), Phytomedicine, doi:10.1016/j.phymed.2024.156279.sciencedirect.com, doi.org.

15. Li et al., Andrographolide suppresses SARS-CoV-2 infection by downregulating ACE2 expression: A mechanistic study, Antiviral Therapy, doi:10.1177/13596535241259952.sagepub.com, doi.org.

16. Low et al., The wide spectrum anti-inflammatory activity of andrographolide in comparison to NSAIDs: a promising therapeutic compound against the cytokine storm, bioRxiv, doi:10.1101/2024.02.21.581396.biorxiv.org, doi.org.

17. Wan et al., Synergistic inhibition effects of andrographolide and baicalin on coronavirus mechanisms by downregulation of ACE2 protein level, Scientific Reports, doi:10.1038/s41598-024-54722-5.nature.com, doi.org.

18. Siridechakorn et al., Inhibitory efficiency of Andrographis paniculata extract on viral multiplication and nitric oxide production, Scientific Reports, doi:10.1038/s41598-023-46249-y.nature.com, doi.org.

19. Mohd Abd Razak et al., In Vitro Anti-SARS-CoV-2 Activities of Curcumin and Selected Phenolic Compounds, Natural Product Communications, doi:10.1177/1934578X231188861.sagepub.com, doi.org.

20. Pu et al., The effects and mechanisms of the anti-COVID-19 traditional Chinese medicine, Dehydroandrographolide from Andrographis paniculata (Burm.f.) Wall, on acute lung injury by the inhibition of NLRP3-mediated pyroptosis, Phytomedicine, doi:10.1016/j.phymed.2023.154753.sciencedirect.com, doi.org.

a. The main protease or M^pro, also known as 3CL^pro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting M^pro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.

b. Calu-3 is a human lung adenocarcinoma cell line with moderate ACE2 and TMPRSS2 expression and SARS-CoV-2 susceptibility. It provides a model of the human respiratory epithelium, but many not be ideal for modeling early stages of infection due to the moderate expression levels of ACE2 and TMPRSS2.

c. A549 is a human lung carcinoma cell line with low ACE2 expression and SARS-CoV-2 susceptibility. Viral entry/replication can be studied but the cells may not replicate all aspects of lung infection.

d. HUVEC (Human Umbilical Vein Endothelial Cells) are primary endothelial cells derived from the vein of the umbilical cord. They are used to study vascular biology, including inflammation, angiogenesis, and viral interactions with endothelial cells.

e. An outbred multipurpose breed of albino mouse used extensively in medical research.

f. A rodent model widely used in infectious disease research due to their susceptibility to viral infections and similar disease progression to humans.

Thomas et al., 29 Apr 2024, peer-reviewed, 4 authors. Contact: jsatija11@gmail.com.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Andrographol..All

Cheminformatics approach to identify andrographolide derivatives as dual inhibitors of methyltransferases (nsp14 and nsp16) of SARS-CoV-2

Jobin Thomas, Anupam Ghosh, Shivendu Ranjan, Jitendra Satija

Scientific Reports, doi:10.1038/s41598-024-58532-7

The Covid-19 pandemic outbreak has accelerated tremendous efforts to discover a therapeutic strategy that targets severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to control viral infection. Various viral proteins have been identified as potential drug targets, however, to date, no specific therapeutic cure is available against the SARS-CoV-2. To address this issue, the present work reports a systematic cheminformatic approach to identify the potent andrographolide derivatives that can target methyltransferases of SARS-CoV-2, i.e. nsp14 and nsp16 which are crucial for the replication of the virus and host immune evasion. A consensus of cheminformatics methodologies including virtual screening, molecular docking, ADMET profiling, molecular dynamics simulations, free-energy landscape analysis, molecular mechanics generalized born surface area (MM-GBSA), and density functional theory (DFT) was utilized. Our study reveals two new andrographolide derivatives (PubChem CID: 2734589 and 138968421) as natural bioactive molecules that can form stable complexes with both proteins via hydrophobic interactions, hydrogen bonds and electrostatic interactions. The toxicity analysis predicts class four toxicity for both compounds with LD 50 value in the range of 500-700 mg/kg. MD simulation reveals the stable formation of the complex for both the compounds and their average trajectory values were found to be lower than the control inhibitor and protein alone. MMGBSA analysis corroborates the MD simulation result and showed the lowest energy for the compounds 2734589 and 138968421. The DFT and MEP analysis also predicts the better reactivity and stability of both the hit compounds. Overall, both andrographolide derivatives exhibit good potential as potent inhibitors for both nsp14 and nsp16 proteins, however, in-vitro and in vivo assessment would be required to prove their efficacy and safety in clinical settings. Moreover, the drug discovery strategy aiming at the dual target approach might serve as a useful model for inventing novel drug molecules for various other diseases.

Author contributions J.T. and J.S. contributed to the study conceptualization and design and were involved in material preparation, data collection and analysis. A.G. and S.R. were involved in molecular dynamics simulations study for providing computational server access. The initial main draft of the manuscript was written by J.T., with additions and revisions from J.S. and S.R. All the authors read and approved the final manuscript. Competing interests The authors declare no competing interests. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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DOI record: { "DOI": "10.1038/s41598-024-58532-7", "ISSN": [ "2045-2322" ], "URL": "http://dx.doi.org/10.1038/s41598-024-58532-7", "abstract": "AbstractThe Covid-19 pandemic outbreak has accelerated tremendous efforts to discover a therapeutic strategy that targets severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to control viral infection. Various viral proteins have been identified as potential drug targets, however, to date, no specific therapeutic cure is available against the SARS-CoV-2. To address this issue, the present work reports a systematic cheminformatic approach to identify the potent andrographolide derivatives that can target methyltransferases of SARS-CoV-2, i.e. nsp14 and nsp16 which are crucial for the replication of the virus and host immune evasion. A consensus of cheminformatics methodologies including virtual screening, molecular docking, ADMET profiling, molecular dynamics simulations, free-energy landscape analysis, molecular mechanics generalized born surface area (MM-GBSA), and density functional theory (DFT) was utilized. Our study reveals two new andrographolide derivatives (PubChem CID: 2734589 and 138968421) as natural bioactive molecules that can form stable complexes with both proteins via hydrophobic interactions, hydrogen bonds and electrostatic interactions. The toxicity analysis predicts class four toxicity for both compounds with LD50 value in the range of 500–700 mg/kg. MD simulation reveals the stable formation of the complex for both the compounds and their average trajectory values were found to be lower than the control inhibitor and protein alone. MMGBSA analysis corroborates the MD simulation result and showed the lowest energy for the compounds 2734589 and 138968421. The DFT and MEP analysis also predicts the better reactivity and stability of both the hit compounds. Overall, both andrographolide derivatives exhibit good potential as potent inhibitors for both nsp14 and nsp16 proteins, however, in-vitro and in vivo assessment would be required to prove their efficacy and safety in clinical settings. 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