Antiviral screening of seaweed native fucoidan and its derivatives against dengue virus NS2B/NS3 Protease (3L6P) and Methyltranferase (MTase -1L9K); An In-silico docking, ADMET and molecular dynamic study

Author: Saravanan Muniyappan, Kothai Ramalingam, D. Vinod Kumar and Arul Balasubramanian

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Abstract

Dengue virus (DENV) infections are the major life threat around the globe with millions of people life is at risk. The cure for DENV infection lays an hectic challemge due to the lack of Antidengue drugs or vaccines which had lead to the enormous demand for a potent lead molecules for the cure, prophylaxis and treatment of Dengue infections. Here an in-silico docking work on native seaweed fucoidan and its derivatives in structure-function investigation of DENV protease and Methyltransferase, the largest non-structural protein of DENV, which is responsible for replication of the viral genome, RNA capping and suppression of host interferon responses was presented. DENV-1 NS2B/NS3 Protease (3L6P) and Methyltranferase (MTase -1L9K) was designated as a prime targets because of its major role in the viral replication cycle. Theses enzymes were selected for the research on antiviral drugs. The sulfated polysaccharide Fucoidan was derived from brown seaweed Stoechospermum marginatum. It was subjected to acid hydrolysis to yield low molecular weight fucoidan monomer and it was characterised by FTIR, NMR, and Mass spectroscopic techniques. The SMFUC molecule was designed to yield 40 derivatives by the structural modification of the two methyl (-CH3) and two hydroxyl (-OH) of the native fucoidan. The methyl moieties were converted to carboxyl group and it was further converted to its ester, amide, aldehyde, acid chloride and ketone, the hydroxyl groups were acetylated, benzoylated, aminated, sulphated and phosphorylated. Further Desulphated SMFUC was designed for the Insilco docking, ADMET, MMSD and Molecular dynamic study against DENV-1 NS2B/NS3 Protease 3L6P and DENV-2 1L9K Methyltranferase. 3,4-diacetyl fucoidan showed highest ligand binding affinity GLIDE score of -9.849 kcal/mol against DENV-1 NS2B/NS3 Protease (3L6P) and 3,4-dibenzoyl fucoidan showed more binding affinity against DENV-2 1L9K Methyltranferase with a GLIDE score of -9.2kcal/mol amongst the native fucoidan and its derivatives. In-silico pharmacokinetic study of the these molecules were screened using SwissADME and sarADMET studies proved that these compounds were well absorbed by GI tract, and do not cross the blood brain barrier, Simulated toxicity simulation studies proved except phosphate fucoidans they are non-toxic and without a metabolic enzyme inhibition activity. Simulated molecular dynamics study against the optimized fucoidans showed a stable RMSD score of 3.8-4.2 for the Acetyl fucoidan-3L6P complex and 1.5-1.8 for Benzoyl fucoidan-1L9K complex. Hence it may conclude that seaweed fucoidan and its derivatives have high antiviral potential against DENV. These molecules might be lead for the emergence of antiviral drugs against DENV infections.

Keywords

Dengue Virus, Fucoidan, in-silico, NS2B/NS3 Protease, Methyl Transferase

Conclusion

The dengue fever is a pathogenic disease caused by the dengue virus communicated through an mosquito vector Aedes aegyptii. Virus replication in host cells is carried out by the DENV non-structural proteins. These non-structural proteins are responsible for viral transcription and replication in the human host cell. In dengue virus, NS2B/NS3 protease is a trypsin-like serine protease and methyltransferase plays an major role in the cleavage of polypeptide, transcribed from the viral genome. The multi-functional property of the viral protease and methytransferase has been utilized as a prime target for drug discovery to cure the dengue fever. The present study focuses on screening and development of inhibitors of the targeted protease and methytranferase. A total of 28 fucoidans were docked against the protease and MTase. In-silico analysis are preferred before conducting any wet lab experimental work, because as it is economical and a less time consuming process. Native fucoidan derived from S.marginatum and its derivatives were docked against DENV-1 NS2B/NS3 Protease and DENV-2 Methyltransferase and the results of molecular docking showed that Acetyl fucoidan inhibit the DEV-1 NS2B/NS3 protease with the binding affinity–9.8kcal/mol, and benzoylated fucoidan exhibited the inhibition against DENV-2 Methyltranferase with the binding affinity of -9.2 kcal/mol. ADMET of the 28 selected phytochemicals revealed that these compounds have very effective drug like properties along with the non-toxic, non-carcinogenic and non-mutagenic nature. The ADMET was considered as end analysis in the screening a large number of phytochemicals, following various reported techniques. All the fucoidans were non-toxic, non-carcinogenic except aminated and phosphate fucoidans and its corresponding desulfated derivatives. The optimized 3,4-diacetyl and 3,4-dibenzoyl fucoidan exhibited a good GI absorption and non permeable to BBB. Hence these compounds are devoid of CNS related side effects. Further they obeyed the Lipinski’s rule of five without any violations and showed good drug likeliness property.MD studies prove the structural ability of the selected fucoidans to bind to the target DENV proteins for an acceptable period of analysis. In the current research we have made an attempt to identify ideal DENV inhibitors that are specifically designed for the cure of DENV infections. The current work aimed to derive a novel molecule from the natural entity called fucoidan isolated from seaweed S.marginatum. These fucoidan derivatives are equally potent when compared with the reported natural biomolecules designed to target DENV strains. Overall, the findings of this study provide important insights into the relationship between fucoidans and the antidengie potentials of its derivatives 3,4-diacetyl fucoidan and 3,4-dibenzoyl fucoidan against DENV1 NS2B/NS3 Protease (3L6P) and against DENV2 Methyltranferase (MTase -1L9K) respectively. The goal of finding a cure for dengue in the next decade is highly feasible, judging from the encouraging Antidengue activity of fucoidan derivative against the DENV2 strain. It was assured and hope that an efficacious anti-dengue fucoidan derivative in the foreseeable future. The future scope Indeed is to conduct in-vitro screening against live DENV strains to test the antiviral potential of the fucoidans.

References

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How to cite this article

Saravanan Muniyappan, Kothai Ramalingam, D. Vinod Kumar and Arul Balasubramanian (2023). Antiviral screening of seaweed native fucoidan and its derivatives against dengue virus NS2B/NS3 Protease (3L6P) and Methyltranferase (MTase -1L9K); An In-silico docking, ADMET and molecular dynamic study. Biological Forum – An International Journal, 15(5): 1144-1155.