Molecular activity of bioactive phytocompounds for inhibiting host cell attachment and membrane fusion interacting with West Nile Virus envelope glycoprotein

West Nile virus is an arbovirus primarily spread by mosquitoes, which are the principal carriers and belong to the Flaviviridae category. This widespread disease lacks specific treatments despite its potential lethality, urgently demanding novel pharmaceutical research and development aims to prevent severe or long-term complications and improve overall outcomes. Pandemic awareness, increasing global incidence, fatal illness effects, expenses associated with outbreaks, reducing suffering, and other broader implications highlight the study’s wider significance. Drug design as a novel treatment approach to reduce the risk of resistance to the virus resulting from overuse of broad-spectrum antiviral therapies for unrelated viral diseases has been evaluated using computational techniques. Initially, molecular docking targeted the envelope glycoprotein of the WNV, utilizing a set of 5375 phytochemicals found in the IMPPAT database. Their binding affinities were −7.464, −5.802, −5.617, and −4.92, kcal/mol for CID: 359 (Phloroglucinol), 9064 (Cianidanol), 25310 (L-Rhamnose), and 492405 (Favipiravir), respectively. The lead compounds and the control ligand both bind at the common active site of the macro-molecule, as evidenced by their interactions with the same amino acid residues at LEU281, ASN47, THR282, SER29, MET48, MET46, and MET45, correspondingly. In post-docking MM-GBSA the negative binding energy of the P-L complex for the compounds CIDs: 359, 9064, 25310, and 492405 (control) were −29.16, −33.45, −32.02, and −3.16 kcal/mol, correspondingly. The selected compounds are secure and efficient since they demonstrate excellent toxicological and Pk characteristics. The compounds were further evaluated to confirm their stability and binding affinity to the target protein by molecular dynamics simulation (RMSD, RMSF, Rg, SASA, H-bond, P-L, and L-P contact). Following this, principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM) studies were conducted using the MD trajectory data. The ligands evaluated in this study demonstrated considerable stability of the proteins’ binding site when complexed with CID: 9064 and CID: 25310, respectively, in the MD simulation, which also revealed a high negative binding free energy value, indicating a robust interaction between the target and lead compounds. The three principal components (PC1, PC2, PC3) for the lead compounds corresponding to CID: 9064 (40.37%, 23.02%, and 8.82%) and CID: 25310 (73.04%, 10.06%, and 3.77%), respectively, indicate that their complexes are more stable than the other L-P complexes. Consequently, both the compounds derived from the plants Tamarindus indica and Plantago ovate, respectively, may potentially impede the viral activity of the WNV envelope glycoprotein, indicating the possibility of these compounds as prospective phytochemical therapeutic candidates. This preclinical study can be used in further drug development processes, including in vivo studies and animal trials.