Marinelli Luciana, Cosconati Sandro, Steinbrecher Thomas, Limongelli Vittorio, Bertamino Alessia, Novellino Ettore, Case David A
Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy.
ChemMedChem. 2007 Oct;2(10):1498-510. doi: 10.1002/cmdc.200700091.
NMDA receptors are glutamate-gated ion channels (iGluRs) that are involved in several important physiological functions such as neuronal development, synaptic plasticity, learning, and memory. Among iGluRs, NMDA receptors have been perhaps the most actively investigated for their role in chronic neurodegeneration such as Alzheimer's, Parkinson's, and Huntington's diseases. Recent studies have shown that the NTD of subunit NR2B modulates ion channel gating through the binding of allosteric modulators such as the prototypical compound ifenprodil. In the present paper, the construction of a three-dimensional model for the NR2B modulatory domain is described and docking calculations allow, for the first time, definition of the ifenprodil binding pose at an atomic level and fully explain all the available structure-activity relationships. Moreover, in an attempt to add further insight into the ifenprodil mechanism of action, as it is not completely clear if it binds and stabilizes an open or a closed conformation of the NR2B modulatory domain, a matter, which is fundamental for the rational design of NMDA antagonists, MD simulations followed by an MM-PBSA analysis were performed. These calculations reveal that the closed conformation of the R1-R2 domain, rather than the open, constitutes the high affinity binding site for ifenprodil and that a profound stabilization of the closed conformation upon ifenprodil binding occurs. Thus, for a rational design and/or for virtual screening experiments, the closed conformation of the R1-R2 domain should be taken into account and our 3D model can provide valuable hints for the design of NR2B-selective antagonists.
NMDA受体是谷氨酸门控离子通道（离子型谷氨酸受体），参与多种重要的生理功能，如神经元发育、突触可塑性、学习和记忆。在离子型谷氨酸受体中，NMDA受体因其在慢性神经退行性疾病（如阿尔茨海默病、帕金森病和亨廷顿病）中的作用，可能是研究最为活跃的。最近的研究表明，亚基NR2B的N端结构域通过与变构调节剂（如典型化合物ifenprodil）结合来调节离子通道门控。在本文中，描述了NR2B调节结构域三维模型的构建，对接计算首次在原子水平上确定了ifenprodil的结合姿势，并充分解释了所有现有的构效关系。此外，为了进一步深入了解ifenprodil的作用机制，由于尚不完全清楚它是结合并稳定NR2B调节结构域的开放构象还是关闭构象，而这一问题对于合理设计NMDA拮抗剂至关重要，因此进行了分子动力学模拟并随后进行MM-PBSA分析。这些计算表明，R1-R2结构域的关闭构象而非开放构象构成了ifenprodil的高亲和力结合位点，并且ifenprodil结合后关闭构象会发生显著稳定。因此，对于合理设计和/或虚拟筛选实验，应考虑R1-R2结构域的关闭构象，我们的三维模型可为设计NR2B选择性拮抗剂提供有价值的线索。
