Binding Affinity Prediction for Ligands and Receptors Forming Tautomers and Ionization Species: Inhibition of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2)

Treatment of ionization and tautomerism of ligands and
receptors is one of the unresolved issues in structure-based prediction
of binding affinities. Our solution utilizes the thermodynamic master
equation, expressing the experimentally observed association constant
as the sum of products, each valid for a specific ligand–receptor
species pair, consisting of the association microconstant and the
fractions of the involved ligand and receptor species. The microconstants
are characterized by structure-based simulations, which are run for
individual species pairs. Here we incorporated the multispecies approach
into the QM/MM linear response method and used it for structural correlation
of published inhibition data on mitogen-activated protein kinase (MAPK)-activated
protein kinase (MK2) by 66 benzothiophene and pyrrolopyridine analogues,
forming up to five tautomers and seven ionization species under experimental
conditions. Extensive cross-validation showed that the resulting models
were stable and predictive. Inclusion of all tautomers and ionization
ligand species was essential: the explained variance increased to
90% from 66% for the single-species model.