神经介素B受体与拮抗剂、激动剂的分子模拟研究

大鼠神经介素B受体(rat neuromedin B receptor, rNMBR)属于G蛋白偶联受体(G-protein coupled receptor, GPCR) A家族的成员. GPCR的结构特征和在信号传导中的重要作用决定了其可以作为很好的药物靶标. 关于rNMBR与内源性激动剂神经介素B (neuromedin B, NMB)以及与非肽类拮抗剂pd168368作用机制的研究对于合理设计受体药物分子有重要的指导意义. 在这一研究中, 我们使用同源模建, 构建受体的三维结构, 进行分子对接和分子动力学的计算. 基于受体三维结构, 通过10 ns的空载受体、激动剂-受体、拮抗剂-受体的分子动力学模拟, 探讨受体与激动剂与拮抗剂的作用机制. 研究表明rNMB-R中跨膜(transmembrane, TM)螺旋3, 5, 6, 7参与配体的结合. NMB与受体的结合, 使受体转变为活性构象, 而受体同拮抗剂pd168368恰好相反.

Molecular Modeling Study on Neuromedin B Receptor with Agonist and Antagonist

Rat neuromedin B receptor (rNMBR) belongs to the family A of G-protein coupled receptor (GPCR). The unique structure and important role in the signaling transduction of GPCR make them very useful for drug targets. So understanding the regulation mechanisms of rNMBR by its agonists and antago-nists at the atomic level is essential for reasonably designing rNMBR antagonists as drug candidates for treating NMB-mediated diseases. A 3D model of rNMBR was constructed by homology modeling, and then molecular docking and molecular dynamics (MD) simulations were carried out. Based on the 3D structure, regulation mechanisms of rNMBR by agonists and antagonists were investigated via three 10 ns MD simula-tions on the systems of apo-rNMBR, rNMBR-NMB and rNMBR-pd168368. It was found that the ligand was located within the transmembrane regions 3, 5, 6, 7 (TM3, TM5, TM6, TM7) of rNMBR, NMB leading the receptor to its activated state. In contrast, binding of pd168368 to rNMBR locked rNMBR in its inactive state.