West Nile virus (WNV) is a mosquito-borne pathogen of escalating epidemiological importance and a growing global health concern, driven by the climate-associated expansion of its Culex mosquito vectors. Although WNV is an extensively studied flavivirus, most host–pathogen interaction studies focus on static and structural aspects rather than dynamic and functional ones. Delineating phosphorylation-mediated interactions between WNV proteins and human kinases bridges a critical gap by providing important insight into the molecular mechanisms underlying infection. In this study, we investigated potential phosphorylation-mediated interactions between WNV proteins and human kinases using an integrative computational framework combining motif prediction, phosphoproteomic data analysis and structural docking. Key interactions were predicted between viral proteins and regulatory kinases within the AKT-ERK pathway and the AMPK-mediated autophagy, including major network kinases such as RAF1, IKBKB, and ULK1. In addition, experimentally validated phosphorylation sites in viral proteins were found to be associated with multiple candidate host kinases, including MAP2K7 and MAP2K9, suggesting complex regulatory networks. Integration with phosphoproteomic datasets supported the relevance of multiple predicted kinases, including those associated with antiviral responses and translational regulation. Protein–protein docking demonstrated stable, energetically favorable interactions between selected host kinases and viral proteins, particularly the viral polymerase (NS5), helicase (NS3), and NS1. The findings of this study establish a framework for future research on the development of host-directed antiviral strategies.
- Exploring the Potential Human Kinase-Viral Substrate Network of West Nile Virus
- Akash Anil - Yenepoya UniversityAyisha A. Jabbar - Yenepoya UniversityVineetha Shaji - Yenepoya UniversityMuktar Ahmed - King Saud UniversityBristow Ben JosephAromal Monipillil Ajayakumar - Yenepoya UniversityPrashant Kumar Modi - Yenepoya UniversityAbhithaj Jayanandan - Yenepoya UniversitySowmya Soman - Yenepoya UniversityYashwanth Subbannayya (Author) - University of Surrey, School of BiosciencesRajesh Raju (Corresponding Author) - Yenepoya University
- Viruses, Vol.18(8), 825
- MDPI
- 27/07/2026
- 08/2026
- 23/06/2026
- King Saud University (Saudi Arabia, Riyadh) - KSU
- Dr. Mukhtar Ahmed is thankful to the Ongoing Research Funding Program, (ORF-2026-984), King Saud University, Riyadh, Saudi Arabia, for the financial support.
- 991124395502346
- © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
- School of Biosciences
- English
- Journal article
- The study data are available in the article and Supplementary Materials. For further inquiries, contact the corresponding author. The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/v18080825/s1: Supplementary Table S1: Prediction results based on Poll B.G. et al. based on 11 aminoacid centric motif. Supplementary Table S2: Prediction results based on Johnson et al. and Yaron-Barir et al. based on 7 aminoacid centric motif (90th percentile threshold). Supplementary Table S3: Prediction results based on Johnson et al. and Yaron-Barir et al. based on 9 aminoacide centric motif. Supplementary Table S4: Prediction results based on Johnson et al. and Yaron-Barir et al. based on 7 aminoacid centric motif (95th percentile threshold). Supplementary Table S5: Prediction results based on Johnson et al. and Yaron-Barir et al. based on 7 aminoacid centric motif (85th percentile threshold). Supplementary Table S6: Prediction results based on Johnson et al. and Yaron-Barir et al. based on 7 aminoacid centric motif (80th percentile threshold). Supplementary Table S7: Kinases predicted for WNV [strain NY-99 (Taxonomy ID: 1968826)] utilizing Netphos. Supplementary Table S8: Kinases predicted for WNV [strain NY-99 (Taxonomy ID: 1968826)] utilizing Gasphos. Supplementary Table S9: Docking analysis of predicted host kinases with selected WNV proteins. Supplementary Table S10: Interaction analysis between human kinase and WNV protein. Supplementary Table S11: Comparative analysis of kinases identified based on Johnson et al. and Yaron-Barir et al. based on 7 aminoacid centric motif across the 80th, 85th, 90th, and 95th percentile thresholds.