噻吩并嘧啶酮类PDE7抑制剂的特征结构及作用机制研究

基于定量构效关系和分子对接研究理论,以34个噻吩并嘧啶酮类磷酸二酯酶7(PDE7)抑制剂为研究对象,采用比较分子相似性指数法(Co MSIA)和GOLD分子对接法研究其特征结构信息以及与靶标的作用机制。结果表明,所建立Co MSIA模型的预测能力较强(Q2=0.53,R2ncv=0.96,R2pre=0.89),结合分子对接结果还发现,抑制剂与PDE7间的作用力以氢键作用力和π-π堆积作用为主;大体积的亲水性氢键供体R1取代基、亲水性R2取代基有利于化合物活性的增强,且哌啶环上有益于结合氢键的受体基团。所得模型和信息为后续新型PDE7抑制剂的设计开发提供理论指导。

Structural Features and Interaction Mechanism of Thienopyrimidinonesas PDE7 Inhibitors

Based on quantitative structure-activity relationship and molecular docking theory,the structural features and interaction mechanism of 34 thienopyrimidinone derivatives as phosphodiesterase 7 (PDE7) inhibitors were investigated by comparative molecular similarity indices analysis (CoMSIA)and GOLD molecular docking methods.The CoMSIA model shows a strong predictability (Q2 =0.53,R2ncv =0.96,R2pre =0.89).Meanwhile,from the CoMSIA contour maps and docking results,it can be concluded that H-bond and π-π stacking interactions are crucial in determining the binding affinity to PDE7.And R1 groups should select the bulk,hydrophilic and H-bond donor ones.R2 partis the steric sensitive region,introduction of the hydrophilic groups into this region are the excellent options.Furthermore,the substituents acting as H-bond acceptor at piperidine ring are conducive to the activity increase.This model and the derived information may help to provide better understanding of the structure features of PDE7 inhibitors and binding mode between the acceptor and ligands,facilitating corresponding novel inhibitors design.