Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
J Chem Inf Model. 2011 Dec 27;51(12):3254-61. doi: 10.1021/ci200427k. Epub 2011 Nov 22.
Microsomal prostaglandin E synthase-1 (mPGES-1) is a newly recognized therapeutic target for the treatment of inflammation, pain, cancer, atherosclerosis, and stroke. Many mPGES-1 inhibitors have been discovered. However, as the structure of the binding site is not well-characterized, none of these inhibitors was designed based on the mPGES-1 structure, and their inhibition mechanism remains to be fully disclosed. Recently, we built a new structural model of mPGES-1 which was well supported by experimental data. Based on this model, molecular docking and competition experiments were used to investigate the binding modes of four representive mPGES-1 inhibitors. As the inhibitor binding sites predicted by docking overlapped with both the substrate and the cofactor binding sites, mPGES-1 inhibitors might act as dual-site inhibitors. This inhibitory mechanism was further verified by inhibitor-cofactor and inhibitor-substrate competition experiments. To investigate the potency-binding site relationships of mPGES-1 inhibitors, we also carried out molecular docking studies for another series of compounds. The docking results correlated well with the different inhibitory effects observed experimentally. Our data revealed that mPGES-1 inhibitors could bind to the substrate and the cofactor binding sites simultaneously, and this dual-site binding mode improved their potency. Future rational design and optimization of mPGES-1 inhibitors can be carried out based on this binding mechanism.
微粒体前列腺素 E 合酶-1（mPGES-1）是一种新发现的治疗炎症、疼痛、癌症、动脉粥样硬化和中风的治疗靶点。已经发现了许多 mPGES-1 抑制剂。然而，由于结合位点的结构尚未很好地阐明，这些抑制剂都不是基于 mPGES-1 结构设计的，其抑制机制仍有待充分揭示。最近，我们构建了一个新的 mPGES-1 结构模型，该模型得到了实验数据的很好支持。基于该模型，通过分子对接和竞争实验研究了四种代表性的 mPGES-1 抑制剂的结合模式。由于对接预测的抑制剂结合位点与底物和辅因子结合位点重叠，mPGES-1 抑制剂可能是双位点抑制剂。通过抑制剂-辅因子和抑制剂-底物竞争实验进一步验证了这种抑制机制。为了研究 mPGES-1 抑制剂的效力-结合位点关系，我们还对另一系列化合物进行了分子对接研究。对接结果与实验观察到的不同抑制效果很好地相关。我们的数据表明，mPGES-1 抑制剂可以同时与底物和辅因子结合位点结合，这种双位点结合模式提高了它们的效力。未来可以基于这种结合机制对 mPGES-1 抑制剂进行合理的设计和优化。
