An in-silico receptor-pharmacophore based multistep molecular docking and simulation study to evaluate the inhibitory potentials against NS1 of DENV-2

Abstract

DENV-2 strain is the most fatal and infectious of the five dengue virus serotypes. The non-structural protein NS1 encoded by its genome is the most significant protein required for viral pathogenesis and replication inside the host body. Thus, targeting the NS1 protein and designing an inhibitor to limit its stability and secretion is a propitious attempt in our fight against dengue. Four novel inhibitors are designed to target the conserved cysteine residues (C55, C313, C316, and C329) and glycosylation sites (N130 and N207) of the NS1 protein in an attempt to halt the spread of the dengue infection in the host body altogether. Numerous computer-aided drug designing techniques including molecular docking, molecular dynamics simulation, virtual screening, principal component analysis, and dynamic cross-correlation matrix were employed to determine the structural and functional activity of the NS1-inhibitor complexes. From our analysis, it was evident that the extent of structural and atomic level fluctuations of the ligand-bound protein exhibited a declining trend in contrast to unbound protein which was prominently noticeable through the RMSD, RMSF, R_g, and SASA graphs. The ADMET analysis of the four ligands revealed a promising pharmacokinetics and pharmacodynamic profile, along with good bioavailability and toxicity properties. The proposed drugs when bound to the targeted cavities resulted in stable conformations in comparison to their unbound state, implying they have good affinity promising effective drug action. Thus, they can be tested in vitro and used as potential anti-dengue drugs.

Communicated by Ramaswamy H. Sarma

Keywords:

• Non-structural protein 1
• DENV2
• hexamer
• glycosylation
• polymerization

Acknowledgements

The authors would like to thank, Amity Institute of Biotechnology, Amity University, Kolkata, India, for their cooperation. The authors are also grateful to Mr. Prantik Banerjee (A91704120085) from B.Tech Biotechnology, Amity Institute of Biotechnology, Amity University Kolkata for providing infrastructural support to them

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated and studies are available within this manuscript and its Supplementary article.

Additional information

Funding

B.Tech Biotechnology, Amity Institute of Biotechnology, Amity University Kolkata.