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

Ravichandran et al., Biointerface Research in Applied Chemistry, doi:10.33263/BRIAC132.155

Mar 2022

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In Silico study showing that semisynthetic andrographolide derivatives have potential to inhibit SARS-CoV-2 infection by targeting the spike protein and human ACE2 receptor. Docking studies found that derivatives AGP15 and AGP14 had the highest binding affinity for the spike protein (-8.4 and -7.7 kcal/mol respectively) while AGP10 and AGP14 had the highest binding affinity for the ACE2 receptor (-8.3 and -8.2 kcal/mol). The key spike protein residues involved in interactions were Arg355, Arg357, and Phe464, while the key ACE2 residues were Pro135, Glu160, Trp163, Lys689, and Asn690. Authors conclude AGP15 and AGP14 are promising anti-COVID-19 drug candidates that warrant further study.

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.

Ravichandran et al., 28 Mar 2022, Malaysia, peer-reviewed, 2 authors. Contact: ravichandran_v@aimst.edu.my (corresponding author).

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

This Paper Andrographol..All

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

Veerasamy Ravichandran

Biointerface Research in Applied Chemistry, doi:10.33263/briac132.155

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causal factor for the current deadly infectious disease CoVID-19. There is no specific drug available for treating COVID-19 other than some vaccines approved for prevention. However, a lot of research is in progress to prove the anti-COVID-19 potential of natural and synthetic compounds. Objective: The present study was aimed to identify the anti-COVID-19 potential of andrographolide (AGP) derivatives by in-silico molecular interaction study. Seventeen AGP derivatives were screened for drug-likeness, ADME, and toxicity profile using in-silico online tools. Then the filtered AGP were subjected to molecular docking using the PyRx tool integrated with AutoDock Vina software. Compounds AGP 15, 14, and 10 have been identified as promising binding molecules for both S and ACE2, preventing the interaction between S and ACE2. AGP-15 had shown a -8.4 Kcal/mol binding/docking score for S, AGP-10 and 14 showed a -8.3 and -8.2 Kcal/mol binding/docking score for ACE2. Overall results indicated that AGP derivatives 15 and 14 might be the best candidates to battle COVID-19. However, further studies like dynamic molecular studies and pharmacological screenings are essential to confirm the stability and action potential of AGP derivatives 14 and 15 as a lead against COVID-19.

Conflicts of Interest The authors declare no conflict of interest.

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