用于设计、合成及生物学评估尿素/乙酰肼结合噻吩并嘧啶衍生物作为GSK-3β抑制剂的片段合并方法
Fragment merging approach for design, synthesis, and biological assessment of urea/acetyl hydrazide clubbed thienopyrimidine derivatives as GSK-3β inhibitors.
作者信息
Saleh Joseph S, Abd El Hadi Soha R, Ibrahim Hany S, Elrazaz Eman Z, Abouzid Khaled A M
机构信息
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, P.O. Box 11566, Abbassia, Cairo, Egypt.
出版信息
BMC Chem. 2023 Sep 27;17(1):127. doi: 10.1186/s13065-023-01026-w.
New thienopyrimidine derivatives were designed and synthesized as GSK-3β inhibitors based on the structure of active binding site of GSK-3β enzyme. In this study, compounds 6b and 6a were found to be moderate GSK-3β inhibitors with IC 10.2 and 17.3 μM, respectively. Molecular docking study was carried out by docking the targeted compounds in the binding site of the GSK-3β enzyme using the MOE program. Moreover, ADME study was performed to predict certain pharmacokinetic properties. The results showed that all synthesized compounds may not be able to penetrate the blood brain barrier; so, the chances of CNS side effects are predicted to be low. CYP1D6 is predicted to be inhibited by compounds (5a, 5d, 6a, 9a and 9b), So drug-drug interactions are expected upon administration of these compounds.
基于糖原合成酶激酶-3β（GSK-3β）酶活性结合位点的结构，设计并合成了新型噻吩并嘧啶衍生物作为GSK-3β抑制剂。在本研究中，发现化合物6b和6a是中度GSK-3β抑制剂，其IC50分别为10.2和17.3 μM。使用MOE程序将靶向化合物对接至GSK-3β酶的结合位点进行分子对接研究。此外，进行了药物代谢动力学（ADME）研究以预测某些药代动力学性质。结果表明，所有合成化合物可能无法穿透血脑屏障；因此，预计中枢神经系统副作用的可能性较低。预计化合物（5a、5d、6a、9a和9b）会抑制细胞色素P450 1D6（CYP1D6），所以预计在施用这些化合物时会发生药物相互作用。
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