Combination of system biology to probe the anti-viral activity of andrographolide and its derivative against COVID-19

Khanal et al., RSC Advances, doi:10.1039/D0RA10529E

Dec 2021

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In Silico study showing that andrographolide and 14-deoxy-11,12-didehydroandrographolide from Andrographis paniculata modulate immune pathways and bind to SARS-CoV-2 papain-like protease, main protease, and spike protein. Authors find that both compounds regulate immune pathways including chemokine signaling, Rap1 signaling, and cytokine-cytokine receptor interaction. Molecular docking predicts that andrographolide binds more strongly than 14-deoxy-11,12-didehydroandrographolide to the viral proteins, with hydrogen bonding to key residues.

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

12 In Silico studies1-12

8 In Vitro studies1,13-19

2 In Vivo animal studies16,19

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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. Chaopreecha et al., Proteomic Analysis Identifies the Glutathione Synthesizing Enzyme Gclc as an Andrographolide Target and a Protective Factor Against Sars-Cov-2 Infection, Elsevier BV, doi:10.2139/ssrn.4876852.ssrn.com, doi.org.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

Khanal et al., 31 Dec 2021, peer-reviewed, 9 authors. Contact: manish.nriashrd@gmail.com, shailendra.gurav@nic.in.

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

This Paper Andrographol..All

Combination of system biology to probe the anti-viral activity of andrographolide and its derivative against COVID-19

Pukar Khanal, Yadu Nandan Dey, Rajesh Patil, Rupesh Chikhale, Manish M Wanjari, Shailendra S Gurav, B M Patil, Bhavana Srivastava, Sudesh N Gaidhani

RSC Advances, doi:10.1039/d0ra10529e

The present study aimed to investigate the binding affinity of andrographolide and its derivative i.e., 14deoxy-11,12-didehydroandrographolide with targets related to COVID-19 and their probable role in regulating multiple pathways in COVID-19 infection. SMILES of both compounds were retrieved from the PubChem database and predicted for probably regulated proteins. The predicted proteins were queried in STRING to evaluate the protein-protein interaction, and modulated pathways were identified concerning the KEGG database. Drug-likeness and ADMET profile of each compound was evaluated using MolSoft and admetSAR 2.0, respectively. Molecular docking was carried using Autodock 4.0. Andrographolide and its derivative were predicted to have a high binding affinity with papain-like protease, coronavirus main proteinase, and spike protein. Molecular dynamics simulation studies were performed for each complex which suggested the strong binding affinities of both compounds with targets. Network pharmacology analysis revealed that both compounds modulated the immune system by regulating chemokine signaling, Rap1 signaling, cytokine-cytokine receptor interaction, MAPK signaling, NF-kappa B signaling, RAS signaling, p53 signaling, HIF-1 signaling, and natural killer cellmediated cytotoxicity. The study suggests strong interaction of andrographolide and 14-deoxy-11,12didehydroandrographolide against COVID-19 associated target proteins and exhibited different immunoregulatory pathways.

Author contributions MMW and BMP: conceptualization, supervision, investigation; RVC and RBP: molecular docking and dynamics studies; PK and YDD: network pharmacology and analysis; SNG and BV: methodology, soware data analysis; SSG and RBP: writing-original dra preparation; MMW and SSG: formal analysis, visualization, reviewing and editing. Ethical statement This study doesn't include any animal or human study. Conflicts of interest The authors declare no competing interests.

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