Chauhan Navneet, Gajjar Anuradha, Basha Syed Hussain
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382 481, Gujarat, India.
Department of Pharmaceutical Chemistry, Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa 388 421, Gujarat, India.
Bioinformation. 2016 Nov 30;12(10):391-395. doi: 10.6026/97320630012391. eCollection 2016.
Glycogen synthase kinase-3 (GSK-3) is a multitasking serine/threonine protein kinase, which is associated with the pathophysiology of several diseases such as diabetes, cancer, psychiatric and neurodegenerative diseases. Tideglusib is a potent, selective, and irreversible GSK-3 inhibitor that has been investigated in phase II clinical trials for the treatment of progressive supranuclear palsy and Alzheimer's disease. In the present study, we performed pharmacophore feature-based virtual screening for identifying potent targetspecific GSK-3 inhibitors. We found 64 compounds that show better GSK-3 binding potentials compared with those of Tideglusib. We further validated the obtained binding potentials by performing 20-ns molecular dynamics simulations for GSK-3 complexed with Tideglusib and with the best compound found via virtual screening in this study. Several interesting molecular-level interactions were identified, including a covalent interaction with Cys199 residue at the entrance of the GSK-3 active site. These findings are expected to play a crucial role in the binding of target-specific GSK-3 inhibitors.
糖原合酶激酶-3（GSK-3）是一种多功能丝氨酸/苏氨酸蛋白激酶，与多种疾病的病理生理学相关，如糖尿病、癌症、精神疾病和神经退行性疾病。 Tideglusib是一种强效、选择性和不可逆的GSK-3抑制剂，已在治疗进行性核上性麻痹和阿尔茨海默病的II期临床试验中进行了研究。在本研究中，我们基于药效团特征进行虚拟筛选，以鉴定强效的靶向特异性GSK-3抑制剂。我们发现64种化合物与Tideglusib相比显示出更好的GSK-3结合潜力。我们通过对与Tideglusib以及本研究中通过虚拟筛选发现的最佳化合物复合的GSK-3进行20纳秒的分子动力学模拟，进一步验证了获得的结合潜力。鉴定出了几种有趣的分子水平相互作用，包括与GSK-3活性位点入口处的Cys199残基的共价相互作用。这些发现有望在靶向特异性GSK-3抑制剂的结合中发挥关键作用。
