Ligand Accessibility Insights to the Dengue virus NS3-NS2B Protease Assessed by long-timescale Molecular Dynamics Simulations

Dengue is a tropical disease caused by the dengue virus (DENV), with an estimate of 300 million new cases every year. Due to the limited vaccine efficiency and absence of effective antiviral treatment, new drug candidates are urgently needed. DENV NS3-NS2B protease complex is essential for viral post-translational processing and maturation, and this enzyme has been extensively studied as a relevant drug target. Crystal structures often underestimate NS3-NS2B flexibility, whereas they can adopt different conformational states depending on the bound substrate. We conducted molecular dynamics simulations (similar to 30 mu s) with a non- and covalently bound inhibitor to understand the conformational changes in the DENV-3 NS3-NS2B complex. Our results show that the open-closing movement of the protease exposes multiple druggable subpockets that can be investigated in later drug discovery efforts.

Automated summary

Dengue is a tropical disease caused by the dengue virus, with an estimated 300 million new cases each year. Due to limited vaccine efficacy and lack of effective antiviral treatment, new drug candidates are urgently needed. Molecular dynamics simulations were conducted to study the conformational changes in the DENV-3 NS3-NS2B complex, revealing multiple druggable subpockets that can be explored in drug discovery efforts.