Department of Chemistry, College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China.
J Phys Chem B. 2010 Dec 9;114(48):16020-8. doi: 10.1021/jp1086416. Epub 2010 Nov 15.
Phosphodiesterase-2 (PDE2) is a key enzyme catalyzing hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) that serve as intracellular second messengers. PDE2 has been recognized as an attractive drug target, and selective inhibitors of PDE2 are expected to be promising candidates for the memory enhancer, antidepressant, and anxiolytic agent. In the present study, we examined the detailed binding structures and free energies for PDE2 interacting with a promising series of inhibitors, i.e., benzo[1,4]diazepin-2-one derivatives, by carrying out molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and binding energy decompositions. The computational results provide valuable insights into the detailed enzyme-inhibitor binding modes including important intermolecular interactions, e.g., the π-π stacking interactions with the common benzo[1,4]diazepin-2-one scaffold of the inhibitors, hydrogen bonding and hydrophobic interactions with the substituents on the benzo[1,4]diazepin-2-one scaffold. Future rational design of new, more potent inhibitors of PDE2 should carefully account for all of these favorable intermolecular interactions. By use of the MD-simulated binding structures, the calculated binding free energies are in good agreement with the experimental activity data for all of the examined benzo[1,4]diazepin-2-one derivatives. The enzyme-inhibitor binding modes determined and the agreement between the calculated and experimental results are expected to be valuable for future rational design of more potent inhibitors of PDE2.
磷酸二酯酶 2（PDE2）是一种关键的酶，能够催化环腺苷酸（cAMP）和环鸟苷酸（cGMP）的水解，这两种物质作为细胞内的第二信使。PDE2 已被认为是一个有吸引力的药物靶点，PDE2 的选择性抑制剂有望成为记忆增强剂、抗抑郁药和抗焦虑药物的有前途的候选药物。在本研究中，我们通过进行分子对接、分子动力学（MD）模拟、结合自由能计算和结合自由能分解，研究了 PDE2 与一系列有前途的抑制剂（即苯并[1,4]二氮杂-2-酮衍生物）相互作用的详细结合结构和自由能。计算结果提供了对详细的酶-抑制剂结合模式的有价值的见解，包括重要的分子间相互作用，例如与抑制剂中常见的苯并[1,4]二氮杂-2-酮支架的π-π堆积相互作用、与苯并[1,4]二氮杂-2-酮支架上取代基的氢键和疏水相互作用。未来对 PDE2 新的、更有效的抑制剂的合理设计应仔细考虑所有这些有利的分子间相互作用。通过使用 MD 模拟的结合结构，计算出的结合自由能与所有测试的苯并[1,4]二氮杂-2-酮衍生物的实验活性数据非常吻合。确定的酶-抑制剂结合模式以及计算结果与实验结果的一致性，有望为未来更有效的 PDE2 抑制剂的合理设计提供有价值的信息。
