In-silico antiviral screening of native seaweed fucoidan and its derivatives against dengue virus-2 RNA dependant RNA polymerase (RdRp)

Abstract

Dengue virus (DENV) infections are a major life threat around the globe with millions of people's life is at risk. The lack of Antidengue drugs and vaccines demands lead molecules for the treatment of Dengue infections. DENV-2 RNA Dependant RNA polymerase (RdRp) was designated as the prime target because of its major role in the viral replication cycle. The purpose of the study is to isolate fucoidan and perform logical and acceptable structural modification of fucoidan for the in-silico screening against DENV for the treatment of DENV DENV-2 NS5 RdRp 6IZY RdRp enzyme was 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 denoted as SMFUC. SMFUC was characterized by spectroscopic studies like FTIR, NMR, and Mass spectroscopy. The SMFUC molecule was designed to yield its derivatives by the structural modification of the two 2 methyl (–CH3) and two hydroxyls (–OH) of the native fucoidan. The methyl moieties were converted to the carboxyl group, and it was further converted to its ester, amide, aldehyde, acid chloride, and ketone, the hydroxyl groups were acetylated, benzoylated, and phosphorylated. Further, Desulphate SMFUC was designed for the Insilco docking, ADMET, MMSD, and Molecular dynamic study against DENV RdRp 6IZY. SMFUC SMFUC1, SMFUC2, SMFUC3, SMFUC4, and SMFUC5 showed ligand binding affinity GLIDE scores in the range of −5.03 to −7.67541 kcal/mol against DENV-2 RdRp 6IZY amongst the native fucoidan and its derivatives. SMFUC2 showed the highest ligand binding affinity of −7.657 kcal/mol. In-silico pharmacokinetic studies of these molecules were screened using SwissADME studies and sarADMET and it was proved that these compounds were well absorbed by the GI tract and do not cross the blood–brain barrier. Simulated toxicity simulation studies proved that except for aminated, sulfated fucoidans they are non-toxic and without a metabolic enzyme inhibition activity. A simulated molecular dynamics study against the optimized fucoidans showed an RMSD score of 1.5, which indicated the ideal interaction of the fucoidan against DENV-2 RdRp. Hence, it may be concluded that seaweed fucoidan and its derivatives have high antiviral potential against DENV-2 cell wall proteins. Hence these molecules might be a lead for the emergence of antiviral drugs against DENV-2 infections.