BACKGROUND Glycogen synthase kinase-3 (GSK3) is associated with various key biological processes and has been considered as an important therapeutic target for the treatment of many diseases. Great efforts have been made on the development of GSK3 inhibitors, especially ATP-competitive GSK3β inhibitor, but it is still a great challenge to develop selective GSK3β inhibitors because of the high sequence homology with other kinases. OBJECTIVE In order to reveal the selectivity mechanisms of GSK3β inhibition at the molecular level, a series of ATP-competitive GSK3β inhibitor was analyzed by a systematic computational method, combining 3DQSAR, molecular docking, molecular dynamic simulations and free energy calculations. METHODS Firstly, 3D-QSAR with CoMFA was built to explore the general structure activity relationships. Secondly, CDOCKER and Flexible docking were employed to predicted the reasonable docking poses of all studied inhibitors. And then, both GSK3β and CDK2 complexes were selected to conduct molecular dynamics simulations. Finally, the free energy calculations were employed to find the key selective-residues. RESULTS CoMFA model suggested the steric, hydrophobic fields play key roles in the bioactivities of inhibitors, and the binding mechanisms were well analyzed through molecular docking. The binding free energies predicted are in good agreement with the experimental bioactivities and the free energy calculations showed that the binding of GSK3β/inhibitors was mainly contributed from hydrogen bonding and hydrophobic interaction. CONCLUSION Some key residues for selective binding were highlighted, which may afford important guidance for the rational design of novel ATP-competitive GSK3β inhibitors.

中文翻译：

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通过3DQSAR，分子对接，分子动力学模拟和自由能计算研究糖原合成酶激酶3β（GSK3β）与吡嗪ATP竞争性抑制剂的选择性机理。

背景技术糖原合酶激酶3（GSK3）与各种关键的生物学过程有关，并且已经被认为是治疗许多疾病的重要治疗靶标。在开发GSK3抑制剂，特别是与ATP竞争的GSK3β抑制剂方面已经做出了巨大的努力，但是由于与其他激酶的高序列同源性，开发选择性的GSK3β抑制剂仍然是巨大的挑战。目的为揭示在分子水平上抑制GSK3β的选择性机理，结合3DQSAR，分子对接，分子动力学模拟和自由能计算，通过系统的计算方法分析了一系列与ATP竞争的GSK3β抑制剂。方法首先，建立了带有CoMFA的3D-QSAR，以探索一般的结构活性关系。其次，使用CDOCKER和Flexible对接来预测所有研究抑制剂的合理对接姿势。然后，选择GSK3β和CDK2复合物进行分子动力学模拟。最后，利用自由能计算找到关键的选择性残基。结果CoMFA模型表明，空间，疏水域在抑制剂的生物活性中起关键作用，并且通过分子对接对结合机理进行了很好的分析。预测的结合自由能与实验生物活性高度吻合，自由能计算表明，GSK3β/抑制剂的结合主要是由氢键和疏水性相互作用引起的。结论强调了一些选择性结合的关键残基，