Dinakar Subramaniyan, Gurubarath Mani, Dhananjayan Karthik
Department of Pharmacology, PSG College of Pharmacy, Peelamedu, Coimbatore, Tamil Nadu, India.
J Biomol Struct Dyn. 2023 Jul;41(11):4847-4862. doi: 10.1080/07391102.2022.2074143. Epub 2022 May 11.
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.
糖原合酶激酶（GSK）-3β是参与糖原合酶磷酸化的下游信号分子之一，糖原合酶是一种将葡萄糖合成糖原的关键酶。GSK-3β调节神经元结构和功能突触可塑性的一些关键过程。在阿尔茨海默病、帕金森病和肌萎缩侧索硬化症的动物模型中，GSK-3β的下调或抑制可增强长期增强作用和认知功能。有多种化合物可用于抑制GSK-3β，但它们都未在临床实践中用于治疗神经退行性疾病。我们研究的目的是通过模拟研究预测天然存在的1,2-二苯基萘酮类似物在糖原合酶激酶（GSK）-3β的三磷酸腺苷结合位点的分子相互作用和动态行为。在所有1,2-二苯基萘酮类似物中，1,3,5,6-四羟基呫吨酮（排名=1）、secalonic酸F（排名=2）和三羟基-2-（2,3-二羟基-3-甲基丁基）-7-甲氧基-8-（3-甲基-2-丁烯基）呫吨酮（排名=3）的对接分数最低，分别为-12.07、-11.49和-11.24 kcal/mol，解离常数分别为1.37、3.84和5.99 nM。排名第1和第3的配体的分子动力学模拟表明，在整个模拟过程中相互作用稳定，相互作用分析表明，1,2-二苯基萘酮核周围C1、C3、C5和C6处羟基的存在会影响它们在GSK-3β的ATP结合位点的结合亲和力。我们预测，1,3,5,6-四羟基呫吨酮和1,3,6-三羟基-2-（2,3-二羟基-3-甲基丁基）-7-甲氧基-8-（3-甲基-2-丁烯基）呫吨酮可能作为潜在的配体或先导化合物来抑制GSK-3β，并且在缓解神经退行性疾病中也可能发挥重要作用。由拉马斯瓦米·H·萨尔马传达。
