通过对两种JNK3抑制剂进行组合3D-QSAR模型研究实现新型支架的演变
Novel scaffold evolution through combinatorial 3D-QSAR model studies of two types of JNK3 inhibitors.
作者信息
Jung Hoyong, Aman Waqar, Hah Jung-Mi
机构信息
Department of Pharmacy, College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Gyeonggi-do 426-791, Republic of Korea.
Department of Pharmacy, College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Gyeonggi-do 426-791, Republic of Korea; Kohat University of Science & Technology, Kohat, Khyber Pukhtunkhwa, Pakistan.
出版信息
Bioorg Med Chem Lett. 2017 May 15;27(10):2139-2143. doi: 10.1016/j.bmcl.2017.03.063. Epub 2017 Mar 24.
JNK3 is an emerging target for neurodegenerative diseases including AD and PD, with histological selectivity. Specifically, in AD, JNK3 is the main protein kinase for APP phosphorylation, which is an important mechanism for Aβ processing, and a biomarker of Alzheimer's disease. Therefore, targeting JNK3 is a reasonable strategy for drug discovery in neurodegenerative diseases. In order to find a novel scaffold for JNK3 inhibitors, we performed 3D-QSAR modeling studies with two different JNK3 inhibitor series. The CoMFA model was obtained with a q value of 0.806 and an r value of 0.850. Based on CoMFA and CoMSIA models, rational design was conducted and led to a novel scaffold, N-(thiophen-2-yl)-8H-pyrazolo[1,5-a]pyrido[1,2-c]pyrimidine-10-carboxamide.
JNK3是包括阿尔茨海默病（AD）和帕金森病（PD）在内的神经退行性疾病的一个新靶点，具有组织学选择性。具体而言，在AD中，JNK3是淀粉样前体蛋白（APP）磷酸化的主要蛋白激酶，这是β淀粉样蛋白（Aβ）加工的重要机制，也是阿尔茨海默病的一个生物标志物。因此，靶向JNK3是神经退行性疾病药物研发的合理策略。为了找到JNK3抑制剂的新型骨架，我们用两个不同的JNK3抑制剂系列进行了三维定量构效关系（3D-QSAR）建模研究。得到的比较分子场分析（CoMFA）模型的q值为0.806，r值为0.850。基于CoMFA和比较分子相似性指数分析（CoMSIA）模型进行了合理设计，得到了一种新型骨架，即N-（噻吩-2-基）-8H-吡唑并[1,5-a]吡啶并[1,2-c]嘧啶-10-甲酰胺。
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