Drug Information Platform Center, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea.
Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea.
Molecules. 2022 Jun 14;27(12):3825. doi: 10.3390/molecules27123825.
Direct inhibitors of glycogen synthase kinase 3β (GSK3β) have been investigated and reported for the past 20 years. In the search for novel scaffold inhibitors, 3000 compounds were selected through structure-based virtual screening (SBVS), and then high-throughput enzyme screening was performed. Among the active hit compounds, pyrazolo [1,5-a]pyrimidin-7-amine derivatives showed strong inhibitory potencies on the GSK3β enzyme and markedly activated Wnt signaling. The result of the molecular dynamics (MD) simulation, enhanced by the upper-wall restraint, was used as an advanced structural query for the SBVS. In this study, strong inhibitors designed to inhibit the GSK3β enzyme were discovered through SBVS. Our study provides structural insights into the binding mode of the inhibitors for further lead optimization.
直接抑制糖原合酶激酶 3β（GSK3β）的抑制剂已经被研究和报道了 20 年。在寻找新型支架抑制剂的过程中，通过基于结构的虚拟筛选（SBVS）选择了 3000 种化合物，然后进行了高通量酶筛选。在活性命中化合物中，吡唑并[1,5-a]嘧啶-7-胺衍生物对 GSK3β 酶表现出很强的抑制活性，并显著激活了 Wnt 信号通路。通过上壁约束增强的分子动力学（MD）模拟结果被用作 SBVS 的高级结构查询。在这项研究中，通过 SBVS 发现了能够抑制 GSK3β 酶的强抑制剂。我们的研究为抑制剂的结合模式提供了结构上的见解，以进一步进行先导优化。
