Kinase inhibitors often change protonation or tautomer state on binding, MCCE modelling shows
- Multi-conformation continuum electrostatics was applied to 37 co-crystal structures of nine kinase domains with 18 approved inhibitors.
- Protein net charge stayed largely stable on binding, whereas inhibitor charge states frequently shifted up or down.
- Binding can resolve two near-equal solution tautomers into one, creating free-energy differences of a few kcal/mol.
💡 Points
Docking with one fixed protonation state is quietly baked into most of our virtual screening, and this says it can be wrong by kcal/mol for approved drugs. When a scaffold with a tautomerisable heterocycle misbehaves in SAR, I'd now check its bound-state tautomer before blaming the pocket.
Kinase Inhibitors can Change Protonation or Tautomeric State upon Binding ↗