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Molecular docking unveils the potential of andrographolide derivatives against COVID-19: an in silico approach.

ABSTRACT:

Background

The recent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection cause high mortality and there is an emergency need to develop a specific drug to treat the novel coronavirus disease, COVID-19. However, some natural and synthetic products with action against SARS-CoV-2 have been reported in recent research, there is no specific drug available for treating COVID-19. In the present study, molecular interaction analysis was performed for 16 semisynthetic andrographolides (AGP) against 5 SARS-CoV-2 enzymes main protease (Mpro, PDB: 6LU7), papain-like protease (PLpro, PDB: 6WUU), spike glycoprotein (S, PDB: 6VXX), NSP15 endoribonuclease (NSP15, PDB: 6VWW), and RNA-dependent RNA polymerase (RdRp, PDB: 6M71). Moreover, the compounds pharmacokinetic and toxic profiles were also analyzed using computational tools.

Results

The protein-ligand docking score (kcal/mol) revealed that all the tested AGP derivatives showed a better binding affinity towards all the tested enzymes than hydroxychloroquine (HCQ). Meanwhile, all the tested AGP derivatives showed a better binding score with RdRp and S than remdesivir (REM). Interestingly, compounds 12, 14, and 15 showed a better binding affinity towards the all the tested enzyme than AGP, REM, and HCQ. AGP-16 had shown - 8.7 kcal/mol binding/docking score for Mpro, AGP-15 showed - 8.6 kcal/mol for NSP15, and AGP-10, 13, and 15 exhibited - 8.7, - 8.9, and - 8.7 kcal/mol, respectively, for S.

Conclusion

Overall results of the present study concluded that AGP derivatives 14 and 15 could be the best 'lead' candidate for the treatment against SARS-CoV-2 infection. However, molecular dynamic studies and pharmacological screenings are essential to developing AGP derivatives 14 and 15 as a drug against COVID-19.

SUBMITTER: Veerasamy R

PROVIDER: S-EPMC9008396 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Molecular docking unveils the potential of andrographolide derivatives against COVID-19: an in silico approach.

Veerasamy Ravichandran R Karunakaran Rohini R

Journal, genetic engineering & biotechnology 20220414 1

<h4>Background</h4>The recent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection cause high mortality and there is an emergency need to develop a specific drug to treat the novel coronavirus disease, COVID-19. However, some natural and synthetic products with action against SARS-CoV-2 have been reported in recent research, there is no specific drug available for treating COVID-19. In the present study, molecular interaction analysis was performed for 16 semisynthetic androgra ...[more]

PMID: 35420322

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Project description:Background The unique anthropological coronavirus which has been titled as SARS-CoV-2 was originally arisen in late 2019 in Wuhan, China affecting respiratory infection named as COVID-19. Coronavirus is disturbing human life in an exceptional method and has converted a public health global crisis. Natural products are ahead consideration due to the huge beneficial window and effective anti-inflammatory, immunomodulatory, antioxidant and antiviral possessions. Consequently, the present study was intended to display inhibition ability of natural products coumarins and their analogues against SARS coronavirus. Methods The present study, aims to forecast theoretical assembly for the protease of COVID-19 and to discover advance whether this protein may assist as a target for protease inhibitors such as psoralen, bergapten, imperatorin, heraclenin, heraclenol, saxalin, oxepeucedanin, angelicin, toddacoumaquinone, and aesculetin. The docking score of these natural coumarin analogues compared with standard Hydroxychloroquine. Whereas the 3D assembly of main protease of SARS coronavirus was forecast with SWISS MODEL web server, and molecular interaction studies amongst target protein and ligands were done with AutoDock Vina software. Results The study more exposed that all the inhibitors acquired with negative dock energy against the target protein. Molecular docking investigation displayed that natural coumarin analogue toddacoumaquinone displayed a remarkable inhibition ability with the binding energy of ?7.8 kcal/mol than other compounds against main protease of SARS coronavirus in intricate with ?-ketoamide (PDB ID: 5N5O). The synthetic coumarin analogue (1 m) also displayed the comparable inhibition ability with a binding energy of ?7.1 kcal/mol against main protease of SARS coronavirus in intricate with ?-ketoamide. Keeping the overhead results of ADME and toxicity, all tested compounds were recognized as drug-like nature, passing Lipinski’s “Rule of 5” with 0 violation except ?-ketoamide passes Lipinski’s “Rule of 5” with 1 violation MW > 500. The projected constraints are within the assortment of recognized values. Conclusions Based upon the results of the manifold sequence alliance, natural and synthetic coumarin binding sites were preserved. The present in silico examination thus, delivers structural awareness about the protease of COVID-19 and molecular relations with some of the recognised protease inhibitors.

Project description:BackgroundThe amide derivatives of nonsteroidal anti-inflammatory drugs have been reported to possess antitumor activity. The present work describes the synthesis of dexibuprofen amide analogues (4a-j) as potential anticancer agents.MethodsThe title amides (4a-j) were obtained by simple nucleophilic substitution reaction of dexibuprofen acid chloride with substituted amines in good yield and chemical structures were confirmed by FTIR, 1H NMR, 13C NMR and mass spectral data.ResultsThe brine shrimp lethality assay results showed that all of the synthesized compounds are non-toxic to shrimp larvae. The inhibitory effects on tumor growth were evaluated and it was observed that N-(2,5-dichlorophenyl)-2-(4-isobutylphenyl) propionamide (4e) and N-(2-chlorophenyl)-2-(4-isobutylphenyl) propionamide (4g) exhibited excellent antitumor activity compared to all other derivatives. The compound 4e bearing 2,5-dichloro substituted phenyl ring and 4g possesses 2-chloro substituted phenyl ring exhibited 100% inhibition of the tumor growth. The anticancer activity was evaluated against breast carcinoma cell line (MCF-7) and it was observed that derivative 4e exhibited excellent growth inhibition of cancer cells with IC50 value of 0.01±0.002 µm, which is better than the standard drugs. The docking studies against breast cancer type 1 susceptibility protein BRCA1 (PDBID 3K0H) exhibited good binding affinities, which are in good agreement with the wet lab results. The compounds 4e and 4g showed the binding energy values of -6.39 and -6.34 Kcal/mol, respectively. The molecular dynamic (MD) simulation was also carried out to evaluate the residual flexibility of the best docking complexes of compounds 4e and 4g. The MD simulation analysis assured that the 4e formed a more stable complex with the target protein than the 4g. The synthesized amide derivatives exhibited were devoid of gastrointestinal side effects and no cytotoxic effects against human normal epithelial breast cell line (MCF-12A) were found.ConclusionBased upon our wet lab and dry lab findings we propose that dexibuprofen analogue 4e may serve as a lead structure for the design of more potent anticancer drugs.

Dataset Information

Molecular docking unveils the potential of andrographolide derivatives against COVID-19: an in silico approach.

Background

Results

Conclusion

Publications

Molecular docking unveils the potential of andrographolide derivatives against COVID-19: an in silico approach.

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