Pim-1蛋白激酶与3,5-二取代吡唑并吡啶衍生物的分子识别研究

Molecular Recognition Between Pim-1 Protein Kinase and 3,5-disubstituted Pyrazolopyridine Derivatives

具有丝/苏氨酸激酶活性的Pim-1蛋白激酶(Pim-1 protein kinase,PPK)的过度表达能导致肿瘤的发生,是一个有效的抗肿瘤药物作用靶点.对PPK与3,5-二取代吡唑并吡啶衍生物(3,5-Disubstituted pyrazolopyridine derivatives,DPD)的复合物进行了20 ns的分子动力学模拟,从能量角度分析了二者结合的主要驱动力以及I 185在识别过程中的重要作用,并对复合物体系在模拟过程中的构象变化进行了分析.结果表明,PPK的核心区的保守性是其发挥生理功能的重要机制,模拟结果对基于PPK抑制剂的药物设计具有一定参考作用.

Pim-1 kinase,with serine / threonine kinase activity,can lead to tumor formation if it is over expressed,so it is a potential anti-cancer drug target. In this paper,a 20 ns molecular dynamics simulation is performed on the compound of PPK and a 3,5-disubstituted pyrazolopyridine derivative. The main driving force of the compound is analyzed from the perspective of energy. Then,the key function of I 185 in recognition is analyzed independently. Finally,the paper analyzes the conformational changes of the compound in the simulation process. The results show that the conservative property of the core region of PPK is an important mechanism for its physiological function. The simulation results are helpful for the following drug design of inhibitor based on PPK.