Discovery of potential scaffolds for glutaminyl cyclase inhibitors: Virtual screening, synthesis, and evaluation.
Discovery of potential scaffolds for glutaminyl cyclase inhibitors: Virtual screening, synthesis, and evaluation.
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DOI：
10.1016/j.bmc.2023.117542
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发表时间：
2023-12
影响因子：
3.5
通讯作者：
Qingqing Zhou;Jiaxin Cai;Feixia Qin;Jiao Liu;Chenyang Li;Wei Xiong;Yinan Wang;Chenshu Xu;Haiqiang Wu
中科院分区：
文献类型：
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作者：
Qingqing Zhou;Jiaxin Cai;Feixia Qin;Jiao Liu;Chenyang Li;Wei Xiong;Yinan Wang;Chenshu Xu;Haiqiang Wu
谷氨酰胺环化酶(QC)在阿尔茨海默病(AD)的早期阶段起着至关重要的作用，因此抑制QC可能是治疗早期AD的一种有前途的策略。因此，具有新型化学支架的QC抑制剂可能有助于开发更多的抗AD药物。我们从Chemdiv和Enamine数据库中对300万种化合物进行了虚拟筛选，以发现QC抑制剂的潜在支架。通过药效团模型、受体-配体药效团模型和Galahad模型的组合，从基于结构的虚拟筛选中选择了三个支架120974、147706和141449，并通过与锌离子的螯合和对接性质进一步筛选。因此，我们分别以这三种支架为基础，设计合成了三种化合物1、2和3。化合物1和3对QC的IC50分别为14.19±4.21和4.34±0.35μM。我们的结果表明，通过虚拟筛选过程选择的新支架具有作为新型QC抑制剂的潜力。
Glutaminyl cyclase (QC) plays a crucial role in the early stages of Alzheimer’s disease (AD), thus inhibition of QC may be a promising strategy for the treatment of early AD. Therefore, QC inhibitors with novel chemical scaffolds may contribute to the development of additional anti-AD agents. We conducted a virtual screening of 3 million compounds from the Chemdiv and Enamine databases, to discover potential scaffolds for QC inhibitors. Three scaffolds,120974,147706,and141449, were selected from this structure-based virtual screening through a combination of pharmacophore modeling, a receptor-ligand pharmacophore model, and the GALAHAD model, and furtherly filtered by chelation with zinc ion and docking properties. Consequently, three compounds,1,2, and3, were designed and synthesized based on these three scaffolds, respectively. The IC50of compounds1and3against QC were 14.19 ± 4.21 and 4.34 ± 0.35 μM, respectively. Our results indicate that the new scaffolds selected using a virtual screening process exhibit potential as novel QC inhibitors.