Instituto de Quimica Medica-CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
J Med Chem. 2011 Dec 22;54(24):8461-70. doi: 10.1021/jm200996g. Epub 2011 Nov 16.
Glycogen synthase kinase 3 (GSK-3) is an important drug target for human severe unmet diseases. Discovery and/or design of allosteric kinase modulators are gaining importance in this field not only for the increased selectivity of this kind of compounds but also for the subtle modulation of the target. This last point is of utmost importance for the GSK-3 inhibition as a therapeutic approach. GSK-3 activity is completely necessary for life, and only the aberrant overactivity found in the pathologies should be inhibited with its inhibitors treatment. We performed here a search for the druggable sites on the enzyme using the fpocket algorithm with the aim to provide allosteric potential binding sites on it and new clues for further drug discoveries. Moreover, our results allowed us to determine the binding sites of different GSK-3 ATP noncompetitive inhibitors, such as manzamine A and the new small molecule VP 0.7, providing evidence for potential allosteric inhibition of GSK-3.
糖原合酶激酶 3（GSK-3）是治疗人类严重未满足医疗需求疾病的重要药物靶点。在该领域，变构激酶调节剂的发现和/或设计变得越来越重要，不仅因为这类化合物具有更高的选择性，还因为它们能够对靶标进行细微的调节。对于 GSK-3 抑制作为一种治疗方法，后一点至关重要。GSK-3 的活性对生命完全必要，只有在病理中发现的异常过度活性才应该用其抑制剂来抑制。我们在这里使用 fpocket 算法搜索酶上的可成药部位，目的是提供其变构潜在结合部位，并为进一步的药物发现提供新的线索。此外，我们的结果还允许我们确定不同 GSK-3 ATP 非竞争性抑制剂（如曼沙宁 A 和新的小分子 VP 0.7）的结合位点，为 GSK-3 的潜在变构抑制提供了证据。
