ORIGINAL PAPER Binding of BIS like and other ligands with the GSK-3β kinase: a combined docking and MM-PBSA study Nihar R. Jena Received: 4 January 2011 /Accepted: 22 March 2011 /Published online: 11 May 2011 # Springer-Verlag 2011 Abstract 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. Keywords BIS like inhibitors . Docking . Glycogen synthase kinase-3β (GSK-3β) . MM-PBSA . Protein-drug binding Introduction Glycogen synthase kinase-3 (GSK-3) is a serine-threonine kinase [1, 2] that plays various important physiological roles such as signal transduction, cell proliferation, survival and differentiation, apoptosis, transcription, insulin action etc. [3–9] in several organisms. However, presumably, over expression of the GSK-3 kinase activity is lethal [10], which has been implicated in different pathological con- ditions like cancer, neurological disorders, diabetes, and bipolar disorders etc. [11–13]. Association of GSK-3 with various diseases has made it an attractive potential therapeutic target in recent days [1, 14, 15], which have paramount importance in medicinal chemistry [15, 16]. Recently binding affinities of several ligands, e.g., H89, SB203580, Y27632, BIS-3, BIS-8 and UCN1 (Scheme 1) complexed with GSK-3β have been studied by Davies et al. [17]. These ligands are mainly adenosine triphosphate (ATP) competitors [1, 15, 16, 18–20]. It has been found that among these ligands, BIS-8 is associated with highest binding affinity [20]. However, the reason of this specificity has not yet been understood clearly. Furthermore, it is believed that H89, SB203580, Y27632 and UCN1 are specific inhibitors of PKA [21, 22], p38 [23–26], ROCK [27–43] and PDK1 [30] kinases respectively and are helpful for treatment of cancer, Alzheimer and other diseases. Given the fact that all kinases have similar sequence identities at the binding site, it is not understood why above ligands do not inhibit GSK-3β strongly. Although Page and Bate [31] have tried to simulate binding affinities of above ligands complexed with GSK- 3β by using molecular dynamics (MD) and Poisson- Boltzmann surface area analysis (MM-PBSA) studies [32– 35], they have failed to reproduce experimentally measured specificities of these ligands [20]. This discrepancy between the experimental and theoretical studies might have arisen due to the starting structure used for the study that was generated by superposing a ligand on another ligand whose complex structure with GSK-3β is experimentally known. Electronic supplementary material The online version of this article (doi:10.1007/s00894-011-1065-9) contains supplementary material, which is available to authorized users. N. R. Jena (*) Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India e-mail: nrjena@mbu.iisc.ernet.in J Mol Model (2012) 18:631–644 DOI 10.1007/s00894-011-1065-9