作为DYRK1A抑制剂的β-咔啉结构/活性关系的计算与实验评估
Computational & experimental evaluation of the structure/activity relationship of β-carbolines as DYRK1A inhibitors.
作者信息
Drung Binia, Scholz Christoph, Barbosa Valéria A, Nazari Azadeh, Sarragiotto Maria H, Schmidt Boris
机构信息
Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss-Str. 4, 64287 Darmstadt, Germany.
Departamento de Química, Universidade Estadual de Maringá, Avenida Colombo 53790, PR 87020-900 Maringá, Brazil.
出版信息
Bioorg Med Chem Lett. 2014 Oct 15;24(20):4854-60. doi: 10.1016/j.bmcl.2014.08.054. Epub 2014 Sep 2.
DYRK1A has been associated with Down's syndrome and neurodegenerative diseases, therefore it is an important target for novel pharmacological interventions. We combined a ligand-based pharmacophore design with a structure-based protein/ligand docking using the software MOE in order to evaluate the underlying structure/activity relationship. Based on this knowledge we synthesized several novel β-carboline derivatives to validate the theoretical model. Furthermore we identified a modified lead structure as a potent DYRK1A inhibitor (IC50=130 nM) with significant selectivity against MAO-A, DYRK2, DYRK3, DYRK4 & CLK2.
双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）与唐氏综合征和神经退行性疾病有关，因此它是新型药物干预的重要靶点。我们使用分子操作环境（MOE）软件，将基于配体的药效团设计与基于结构的蛋白质/配体对接相结合，以评估潜在的结构/活性关系。基于这一认识，我们合成了几种新型β-咔啉衍生物，以验证理论模型。此外，我们确定了一种修饰的先导结构，作为一种有效的DYRK1A抑制剂（半数抑制浓度[IC50]=130纳摩尔），对单胺氧化酶A（MAO-A）、双特异性酪氨酸磷酸化调节激酶2（DYRK2）、双特异性酪氨酸磷酸化调节激酶3（DYRK3）、双特异性酪氨酸磷酸化调节激酶4（DYRK4）和细胞周期蛋白依赖性激酶样2（CLK2）具有显著的选择性。
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