Prediction of binding affinity of 1,2-diphenyline ketone analogues at adenosine triphosphate binding site of glycogen synthase kinase-3β: a molecular docking and dynamic simulation study

Glycogen synthase kinase (GSK)-3β is one of the downstream signalling molecules involved in phosphorylation of glycogen synthase, a key enzyme involved in the synthesis of glycogen from glucose. GSK-3β regulate some of the critical processes underlying structural and functional synaptic plasticity of neurons. Down regulation or inhibition of GSK-3β enhances long-term potentiation and cognitive functions in animal models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. A number of compounds are available to inhibit GSK-3β, however none of them are in clinical practice to treat neurodegenerative diseases. The aim of our study was to predict the molecular interaction and dynamic behaviour of naturally occurring 1,2-diphenyline ketone analogues at the adenosine triphosphate binding site of glycogen synthase kinase (GSK)-3β through simulation studies. Out of all 1,2-diphenyline ketone analogues,1, 3, 5, 6-Tetrahydroxyxanthone (Rank = 1), Secalonic acid F (Rank = 2), and Trihydroxy-2-(2,3-dihydroxy-3-methylbutyl)-7-methoxy-8-(3-methyl-2-butenyl) xanthone (Rank = 3) were found to exhibit lowest docking score of -12.07, -11.49, and -11.24 kcal/mol with dissociation constant of 1.37, 3.84, and 5.99 nM, respectively. The molecular dynamic simulation of rank 1 and rank 3 ligands indicated stable interaction throughout the simulation and interaction analyses has shown that the presence of hydroxyl groups at C1, C3, C5, and C6 around 1,2 diphenyline ketone nucleus to influence their binding affinity at the ATP-binding site of GSK-3β. We predicted that 1,3,5,6-Tetrahydroxyxanthone and 1, 3, 6-Trihydroxy-2-(2,3-dihydroxy-3-methylbutyl)-7-methoxy-8-(3-methyl-2-butenyl) xanthone may act as a potential ligand or lead compound to inhibit GSK-3β and also may play an important role in alleviating neurodegenerative diseases.Communicated by Ramaswamy H. Sarma.