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-3 beta

作者：Kitamura Kunihiro^*; Tamura Yunoshin; Ueki Tomokazu; Ogata Koji; Noda Shigeho; Himeno Ryutaro; Chuman Hiroshi

来源：Journal of Chemical Information and Modeling, 2014, 54(6): 1653-1660.

DOI：10.1021/ci400719v

Present computational lead (drug)-optimization is lacking in thermodynamic tactics. To examine whether calculation of binding free-energy change (Delta G) is effective for the lead-optimization process, binding Delta Gs of 7-azaindole derivatives to the ATP binding site of glycogen synthase kinase-3 beta (GSK-3 beta) were calculated. The result was a significant correlation coefficient of r = 0.895 between calculated and observed Delta Gs. This indicates that calculated Delta G reflects the inhibitory activities of 7-azaindole derivatives. In addition to quantitative estimation of activity, Delta G calculation characterizes the thermodynamic behavior of 7-azaindole derivatives, providing also useful information for inhibitor optimization on affinity to water molecules.

• 出版日期2014-6
• 单位RIKEN