Page 130 - GPD-4-2

Gene & Protein in Disease

ORIGINAL RESEARCH ARTICLE
Molecular binding of 11q to NS2B–NS3

proteases of dengue and West Nile viruses

Ramprakash Yadav and Nihar Ranjan Jena*
Discipline of Natural Sciences, Indian Institute of Information Technology, Design and Manufacturing,
Jabalpur, Madhya Pradesh, India

Abstract

Dengue virus (DENV) and West Nile virus (WNV) are mosquito-borne pathogens
that cause severe health burdens globally. Despite their impact, no clinically
approved antiviral therapies are currently available. The NS2B–NS3 protease is
essential for viral genome replication in both viruses, increasing viral loads in
infected individuals. Therefore, targeting and inhibiting this protease would
significantly reduce viral replication. In a recent molecular dynamics (MD) simulation
study, N-(((2,6-dibromophenyl) amino) methyl)-4-morpholinobenzamide (11q) was
found to bind more strongly to the NS2B–NS3 protease of the Zika virus (ZIKV)
than SYC–1307, a known ZIKV protease inhibitor. Notably, 11q was also observed to
*Corresponding author: inhibit influenza virus replication. Given the high structural and sequence similarity
Nihar Ranjan Jena of the NS2B–NS3 protease across ZIKV, DENV, and WNV, it was necessary to evaluate
(nrjena@iiitdmj.ac.in) whether 11q can bind to the proteases of DENV and WNV to inhibit their activities.
Citation: Yadav RP, Jena NR. Using molecular docking, MD, and binding free energy studies, we found that 11q
Molecular binding of 11q to NS2B– strongly binds to the NS2B–NS3 proteases of DENV and WNV with binding free
NS3 proteases of dengue and West energies of −15.80 ± 3.34 kcal/mol and −13.13 ± 2.56 kcal/mol, respectively. The
Nile viruses. Gene Protein Dis.
2025;4(2):8293. slightly more favorable binding of 11q to the DENV protease is comparable to that
doi: 10.36922/gpd.8293 observed with the ZIKV protease. Interestingly, the binding affinities of 11q for all
Received: December 30, 2024 three viral proteases surpass that of the ZIKV–SYC–1307 complex. Therefore, it is
proposed that 11q may act as a pan-antiviral agent against ZIKV, DENV, and WNV
1st revised: April 30, 2025
proteases. However, experimental verification of its protease inhibition activities is
2nd revised: May 6, 2025 required before it can be repurposed for therapeutic use against these viral diseases.
3rd revised: May 14, 2025
Accepted: May 14, 2025 Keywords: Dengue virus; West Nile virus; NS2B–NS3 protease; Docking; Molecular
Published online: June 4, 2025 dynamics simulation; Multiple targeting inhibitor
Copyright: © 2025 Author(s).
This is an Open-Access article
distributed under the terms of the
Creative Commons Attribution 1. Introduction
License, permitting distribution,
and reproduction in any medium, Dengue virus (DENV) is a member of the Flaviviridae family and is mainly transmitted
provided the original work is through mosquito bites, particularly by Aedes albopictus and Aedes aegypti. DENV
1
properly cited. has four distinct serotypes (DENV 1 – 4) that are responsible for inducing viral
2
Publisher’s Note: AccScience diseases, primarily in tropical and subtropical territories. DENV infections can
3-5
4
Publishing remains neutral with induce mild to severe effects. Similarly, the West Nile virus (WNV) is another
5-7
regard to jurisdictional claims in
published maps and institutional clinically significant member of the Flaviviridae family that shares several virological
affiliations. and epidemiological features with DENV but exhibits distinct characteristics. WNV is
Volume 4 Issue 2 (2025) 1 doi: 10.36922/gpd.8293