Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India.
J Mol Model. 2012 Feb;18(2):631-44. doi: 10.1007/s00894-011-1065-9. Epub 2011 May 11.
Binding of several bisindolylmaleimide (BIS) like (BIS-3, BIS-8 and UCN1) and other ligands (H89, SB203580 and Y27632) with the glycogen synthase kinase-3 (GSK-3β) has been studied using combined docking, molecular dynamics and Poisson-Boltzmann surface area analysis approaches. The study generated novel binding modes of these ligands that can rationalize why some ligands inhibit GSK-3β while others do not. The relative binding free energies associated with these binding modes are in agreement with the corresponding measured specificities. This study further provides useful insight regarding possible existence of multiple conformations of some ligands like H89 and BIS-8. It is also found that binding modes of BIS-3, BIS-8 and UCN1 with GSK-3β and PDK1 kinases are similar. These new insights are expected to be useful for future rational design of novel, more potent GSK-3β-specific inhibitors as promising therapeutics.
使用组合对接、分子动力学和泊松-玻尔兹曼表面面积分析方法研究了几种双吲哚马来酰亚胺（BIS）类似物（BIS-3、BIS-8 和 UCN1）和其他配体（H89、SB203580 和 Y27632）与糖原合酶激酶-3（GSK-3β）的结合。该研究产生了这些配体的新结合模式，可以合理说明为什么有些配体抑制 GSK-3β，而有些则不抑制。这些结合模式相关的相对结合自由能与相应的实测特异性一致。这项研究进一步提供了有关某些配体（如 H89 和 BIS-8）可能存在多种构象的有用见解。还发现 BIS-3、BIS-8 和 UCN1 与 GSK-3β 和 PDK1 激酶的结合模式相似。这些新的见解有望为未来合理设计新型、更有效的 GSK-3β 特异性抑制剂作为有前途的治疗方法提供有用的信息。
