化学
药物发现
激酶
计算生物学
安普克
对接(动物)
体外
分子模型
组合化学
蛋白激酶A
生物化学
生物
医学
护理部
作者
Wei Zhu,Xiaosong Liu,Qi Li,Feng Gao,Tingting Liu,Xiaojing Chen,Man Zhang,Alex Aliper,Feng Ren,Xiao Ding,Alex Zhavoronkov
标识
DOI:10.1016/j.bmc.2023.117414
摘要
Salt-inducible kinase 2 (SIK2) has been recognized as a potential target for anti-inflammation and anti-cancer therapy. In this paper, based on the binding pose of the reported compound (GLPG-3970, 3) with AlphaFold protein structure, a series of hinge cores were generated via AI-generative models (Chemistry42). After the molecular docking, synthesis, and biological evaluation, a hit molecule (7f) targeting SIK2 was obtained with a novel scaffold. Further SAR exploration led to the discovery of compound 8g with superior potency against SIK2 compared with the reported inhibitors. Furthermore, 8g also demonstrated excellent selectivity over other AMPK kinases, favorable in vitro ADMET profiles and decent cellular activities. This work provides an alternative approach to the discovery of novel and selective kinase inhibitors.
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