Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain.
Instituto de Farmacia Industrial, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur s/n, 15782 Santiago de Compostela, Spain.
Molecules. 2017 Sep 4;22(9):1472. doi: 10.3390/molecules22091472.
Phosphodiesterase (PDE) enzymes regulate the levels of cyclic nucleotides, cAMP, and/or cGMP, being attractive therapeutic targets. In order to modulate PDE activity in a selective way, we focused our efforts on the search of allosteric modulators. Based on the crystal structure of the PDE10A GAF-B domain, a virtual screening study allowed the discovery of new hits that were also tested experimentally, showing inhibitory activities in the micromolar range. Moreover, these new PDE10A inhibitors were able to decrease the nitrite production in LPS-stimulated cells, thus demonstrating their potential as anti-inflammatory agents.
磷酸二酯酶 (PDE) 酶调节环核苷酸 cAMP 和/或 cGMP 的水平，是有吸引力的治疗靶点。为了选择性地调节 PDE 的活性，我们专注于寻找别构调节剂。基于 PDE10A GAF-B 结构域的晶体结构，一项虚拟筛选研究发现了新的苗头化合物，这些化合物也进行了实验测试，显示出微摩尔范围内的抑制活性。此外，这些新的 PDE10A 抑制剂能够减少 LPS 刺激的细胞中亚硝酸盐的产生，从而证明它们具有作为抗炎剂的潜力。
