title: Binding affinity prediction for ligands and receptors forming tautomers and ionization species: inhibition of mitogen-activated protein kinase-activated protein kinase 2 (MK2).
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Vermont Campus, 261 Mountain View Drive, Colchester, Vermont 05446, USA.
authors.forename: Senthil
authors.initials: S
authors.lastname: Natesan
authors.forename: Rajesh
authors.initials: R
authors.lastname: Subramaniam
authors.forename: Charles
authors.initials: C
authors.lastname: Bergeron
authors.forename: Stefan
authors.initials: S
authors.lastname: Balaz
mesh_terms: D003198:Computer Simulation; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007477:Ions; D007536:Isomerism; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D012996:Solutions; D013816:Thermodynamics; D013876:Thiophenes / Q000737:chemistry*; D014867:Water; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007477:Ions; D008024:Ligands; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D011758:Pyrroles; D012996:Solutions; D013876:Thiophenes; D014867:Water; D000099190:MAP-Kinase-Activated Kinase 2