Identification of neo-andrographolide compound targeting NS1 Lys14: an important residue in NS1 activity driving dengue pathogenesis.

Dengue virus is part of the flaviviruses that spread through the Aedes mosquito species and causes vascular leakage and multiple organ failure. The non-structural protein 1 (NS1) is involved in the replication of Dengue virus. The glycosylated dimeric and hexameric form of NS1 is the biologically active form. Therefore, in this study, the NS1 protein was modeled in dimeric form which is predominantly present inside the host cell. The dimeric model was validated and it was glycosylated at ASN130 and ASN207 with oligomannose. This model was simulated for 100 ns to retrieve the global minima structure. The andrographolide and its four derivatives were docked non-specifically against the dimeric glycosylated NS1 protein. The neo-andrographolide compound showed strong interactions with favorable binding energy of -8.2 kcal/mol and electrostatic binding affinity of -8.9 kcal/mol. All docked ligand-protein complexes were simulated for 100 ns. The molecular dynamics simulation analysis comprising of root mean square deviation and fluctuation, the radius of gyration, hydrogen bonding, potential energy, principal component analysis, SASA, DSSP, Free energy Landscape, MM-PBSA and Electrostatic binding affinity revealed about the stability of complex systems. These andrographolide and its derivatives was found to be interacting with Lys14 and this residue was reported as one of the important residues in NS1 activity. Among all compounds, the neo-andrographolide compound has the promising potential to inhibit the activity of the NS1 which is necessary for the Dengue virus replication. HighlightsThe dimeric NS1 protein structure was modeled and glycosylated at ASN130 and ASN 207 with Oligo-mannose.The minimized structure was used for molecular docking studies with andrographolide and its derivatives.The Lys14 residue is well interfered by all compounds but based on molecular dynamics and binding affinity studies, neo-andrographolide compound has the promising potential to inhibit the activity of the NS1.Communicated by Ramaswamy H. Sarma.