title: Binding free-energy calculation is a powerful tool for drug optimization: calculation and measurement of binding free energy for 7-azaindole derivatives to glycogen synthase kinase-3β.
abstract: Present computational lead (drug)-optimization is lacking in thermodynamic tactics. To examine whether calculation of binding free-energy change (ΔG) is effective for the lead-optimization process, binding ΔGs of 7-azaindole derivatives to the ATP binding site of glycogen synthase kinase-3β (GSK-3β) were calculated. The result was a significant correlation coefficient of r = 0.895 between calculated and observed ΔGs. This indicates that calculated ΔG reflects the inhibitory activities of 7-azaindole derivatives. In addition to quantitative estimation of activity, ΔG calculation characterizes the thermodynamic behavior of 7-azaindole derivatives, providing also useful information for inhibitor optimization on affinity to water molecules.
authors.affiliation: Nihon Pharmaceutical University , 10281 Komuro, Ina-cho, Kitaadachi-gun, Saitama 362-0806, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Kitamura
authors.forename: Yunoshin
authors.initials: Y
authors.lastname: Tamura
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ueki
authors.forename: Koji
authors.initials: K
authors.lastname: Ogata
authors.forename: Shigeho
authors.initials: S
authors.lastname: Noda
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Himeno
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chuman
mesh_terms: D001665:Binding Sites; D030562:Databases, Protein; D055808:Drug Discovery; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: C023422:7-azaindole dimer; D007211:Indoles; D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3