Modeling-led design yields a pan-serotype dengue NS4B inhibitor candidate
- Comparative models of the structurally unresolved NS4B across all four dengue serotypes reveal a conserved transmembrane pocket that fits known resistance mutations.
- Docking of the JNJ-series inhibitors fed predictive field-based 3D-QSAR models, which were used to screen bioisosteres and in-house compounds.
- The top candidate, BNJ-495, was extremely potent against serotype 2 with a high selectivity index, and its conserved binding contacts suggest broad-spectrum activity.
💡 Points
A homology-model plus 3D-QSAR workflow that delivers a prospectively validated hit against a membrane protein with no structure is rare, and that is what makes this worth a look. Before I trust 'pan-serotype', I'd want to see the other three serotypes tested and whether the JNJ-series liabilities carried over.
Structure-Guided Design of a Subnanomolar Dengue Virus NS4B Inhibitor ↗