Daggupati Trinath, Pamanji Rishika, Yeguvapalli Suneetha
a Department of Zoology , Sri Venkateswara University , Tirupati , India.
b Department of Computer Science Engineering, Sri Venkateswara University , Tirupati , India.
J Recept Signal Transduct Res. 2018 Aug;38(4):279-289. doi: 10.1080/10799893.2018.1478854. Epub 2018 Jun 27.
Glycogen synthase kinase-3β (GSK3β) has been reported for its impact on multitude biological processes from cell proliferation to apoptosis. The increase in the ratio of active/inactive GSK3β is the major factor associated in the etiology of several psychiatric diseases, diabetes, muscle hypertrophy, neurodegenerative diseases, and some cancers. These findings made GSK3β a promising therapeutic target, and the interest in the discovery, synthesis of novel drugs to effectively attenuate its function with probably no side effects has been increasing in the chronology of GSK3β drug discovery. In the present study, we applied a combination of computational tools on a chemical library for the virtual discovery of their potency to inhibit GSK3β. The chemical library was screened against a set of filters at different levels. Finally, five compounds in the chemical library were found to potentially inhibit GSK3β with no toxic effects. Furthermore, binding mode analysis revealed that all the compounds bound to the ATP site and most of the hydrogen bonding interactions are conserved as in GSK3β structures deposited in PDB.
糖原合酶激酶-3β（GSK3β）因其对从细胞增殖到细胞凋亡等众多生物学过程的影响而被报道。活性/非活性GSK3β比例的增加是与几种精神疾病、糖尿病、肌肉肥大、神经退行性疾病和某些癌症的病因相关的主要因素。这些发现使GSK3β成为一个有前景的治疗靶点，并且在GSK3β药物发现的进程中，对发现、合成能有效减弱其功能且可能无副作用的新型药物的兴趣一直在增加。在本研究中，我们在一个化学文库上应用了多种计算工具，以虚拟方式发现它们抑制GSK3β的效力。该化学文库针对不同水平的一组筛选条件进行了筛选。最后，发现化学文库中的五种化合物具有潜在抑制GSK3β的作用且无毒性作用。此外，结合模式分析表明，所有化合物均与ATP位点结合，并且大多数氢键相互作用与PDB中保存的GSK3β结构中的氢键相互作用一样得以保留。
