A comprehensive protein interaction map and druggability investigation prioritized dengue virus NS1 protein as promising therapeutic candidate

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.