S1 Graphical abstract -

Dengue Virus (DENV) is a serious threat to human life worldwide and is one of the most dangerous vector-borne diseases, causing thousands of deaths annually. We constructed a comprehensive PPI map of DENV with its host Homo sapiens and performed various bioinformatics analyses. We found 1195 interactions between 858 human and 10 DENV proteins. Pathway enrichment analysis was performed on the two sets of gene products, and the top 5 human proteins with the maximum number of interactions with dengue viral proteins revealed noticeable results. The non-structural protein NS1 in DENV had the maximum number of interactions with the host protein, followed by NS5 and NS3. Among the human proteins, HBA1 and UBE2I were associated with 7 viral proteins, and 3 human proteins (CSNK2A1, RRP12, and HSP90AB1) were found to interact with 6 viral proteins. Pharmacophore-based virtual screening of millions of compounds in the public databases was performed to identify potential DENV-NS1 inhibitors. The lead compounds were selected based on RMSD values, docking scores, and strong binding affinities. The top ten hit compounds were subjected to ADME profiling which identified compounds C2 (MolPort-044-180-163) and C6 (MolPort-001-742-737) as lead inhibitors against DENV-NS1. Molecular dynamics trajectory analysis and intermolecular interactions between NS1 and the ligands displayed the molecular stability of the complexes in the cellular environment. The in-silico approaches used in this study could pave the way for the development of potential specie-specific drugs and help in eliminating deadly viral infections. Therefore, experimental and clinical assays are required to validate the results of this study.</div

Fig 10 -

Residue wise percentage SSE analysis of DENV-NS1 protein and SSE contribution of each residue as function of time for 100ns simulation trajectory (A) Per-residue percentage of the DENV-NS1 protein when bound to Molprot_001742737. (B) Per-residue percentage of the DENV-NS1 protein when bound to Molprot_129895261.</p

Binding energy decomposition analysis of bound- DENV-NS1 protein with novel drug candidates using the MMGBSA approach.

Binding energy decomposition analysis of bound- DENV-NS1 protein with novel drug candidates using the MMGBSA approach.</p

Top lead compounds docking in the active site of DENV-NS1.

(A) Pharmacophore model designed for the DENV-NS1 and molecular interactions of top hit compounds according to ADME analysis with the binding pocket of NS1. (B) Molecular interactions of compound C2 with DENV-NS1. (C) Molecular interactions of compound C6 with DENV-NS1.</p

List of human proteins with greatest number of associations with DENV proteins.

List of human proteins with greatest number of associations with DENV proteins.</p

Important statistics of the DENV-human interaction network.

Important statistics of the DENV-human interaction network.</p

Post-simulation RMSD, RMSF, Rg, hydrogen bonds, and β-factor analysis of DENV-NS1 protein in complex with two drug-like compounds from the Molport database.

(A) RMSD of the carbon-alpha of the bound-DENV-NS1 protein complex. (B) RMSD of the selected drug candidates from the Molport database. (C) RMSF of per-residue bound-DENV-NS1 protein. (D) Rg of bound-DENV-NS1 protein. (E) Inter-protein hydrogen bond occupancy of DENV-NS1 protein in complex with lead candidates. (F) Residue-based β-factor of DENV-NS1 protein in complex with lead candidates from the MolPort database.</p

High scoring interacting proteins of dengue virus.

High scoring interacting proteins of dengue virus.</p

KEGG pathway enrichment analysis of the top 30 highly DENV-associated human proteins.

The bar chart shows that the proteins are highly enriched in protein export pathway (enrichment ratio: 0.04). Other pathways include prion diseases, thyroid hormone synthesis, african trypanosmiasis, NF-kappa B signaling pathway and several other disease pathways including measles, malaria and primary immunodeficiency. Excelsheet S1 containing all the interacting proteins of human and DENV proteins. (PNG)</p

Chemical structures of the top hit compounds docked best with the binding pocket of NS1 based on Pharmit scores and RMSD values.

Chemical structures of the top hit compounds docked best with the binding pocket of NS1 based on Pharmit scores and RMSD values.</p