CDK4抑制剂结合机理的计算机辅助研究  

Computer-aided study on the binding mechanism of CDK4 inhibitor

作　　者：张鲁霞 李丰 李燕[1] ZHANG Luxia;LI Feng;LI Yan(School of Chemical Engineering,Dalian University of Technology,Dalian 116024,China;School of Civil Engineering,Henan Institute of Engineering,Zhengzhou 451191,China)

机构地区：[1]大连理工大学化工学院,辽宁大连116024 [2]河南工程学院土木工程学院,河南郑州451191

出　　处：《沈阳药科大学学报》2022年第12期1421-1432,共12页Journal of Shenyang Pharmaceutical University

基　　金：国家自然科学基金重点项目(81530100)。

摘　　要：目的 为新型CDK4抑制剂的合成提供一定指导。细胞周期蛋白依赖性激酶4(CDK4)是丝氨酸/苏氨酸激酶家族的成员之一,同时也是治疗乳腺癌等癌症的重要靶点。此外,CDK4能够调节细胞周期,改变肿瘤微环境,提高肿瘤免疫原性。细胞周期的紊乱和不受控制的增殖与CDK4抑制剂的缺乏息息相关。方法 本文结合三维定量构效关系(3D-QSAR)和分子对接模拟方法,对85个抑制剂分子与CDK4受体之间的相互作用关系进行了深入地探讨。其中基于配体的CoMSIA模型,是通过随机分配训练集和测试集来获得预测结果。此外,借助各力场轮廓图和对接模拟确定了几个关键的结构特征。结果 在这项研究中,我们成功地建立了令人满意的CoMSIA模型(Q^(2)=0.600,R^(2)_(ncv)=0.986,F=371.728,R^(2)_(pre)=0.952)。此外,对接模拟结果表明,这些抑制剂分子在CDK4的ATP位点与之紧密结合,该位点主要由15个氨基酸残基组成,即Glu144、Arg101、Asn145、Ile12、Gln98、Val96、Asp97、Leu147、Asp99、Asp158、Lys142、Ala16、Gly15、Thr177、和Trp179。抑制剂分子在氢键、盐桥、静电和疏水相互作用下呈现出稳定“V”型构象。结论 本文研究了CDK4抑制剂的结构特征与抑制活性间的关系以及配体小分子与CDK4受体之间的结合模式,这将有助于更好地理解该类抑制剂分子的作用机理,并为新型CDK4抑制剂的设计和优化奠定基础。Objective To provide some guidance for the synthesis of novel and efficient CDK4 inhibitors.Cyclin-dependent kinase 4(CDK4) is a member of the serine/threonine kinase family and is also an important target for the treatment of breast cancer and other cancers.In addition, CDK4 can regulate the cell cycle, change the tumor microenvironment, and improve tumor immunogenicity.Cell cycle disruption and uncontrolled proliferation are closely linked to the absence of CDK4 inhibitors.Methods In this paper, we combined three-dimensional quantitative conformational relationship(3 D-QSAR) and molecular docking methods to investigate the interaction between 85 inhibitor molecules and CDK4 receptors.Among them, the ligand-based CoMSIA model is used to obtain prediction results by randomly assigning the training sets and test sets.In further, several key structural features were identified with the help of contour maps of various force field and docking simulations.Results In this study, we successfully established a satisfactory CoMSIA model(Q^(2)=0.600,R^(2)_(ncv)=0.986,F=371.728,R^(2)_(pre)=0.952).Furthermore, docking simulations showed that these inhibitor molecules bind tightly at the ATP site of CDK4,which consists mainly of 15 amino acid residues, namely Glu144,Arg101,Asn145,Ile12,Gln98,Val96,Asp97,Leu147,Asp99,Asp158,Lys142,Ala16,Gly15,Thr177,and Trp179.The inhibitor molecule exhibits a stable “V” conformation under hydrogen bonding, salt bridges, electrostatic and hydrophobic interactions.Conclusion This paper examines the relationship between structural features and inhibitory activity of CDK4 inhibitors and the binding mode between ligand molecules and CDK4 receptors, which will help to better understand the mechanism of action of this class of inhibitor molecules and lay the foundation for the design and optimization of novel CDK4 inhibitors.

关 键 词：三维定量构效关系 细胞周期蛋白依赖性激酶4 抑制剂 分子对接 乳腺癌 

分 类 号：R917[医药卫生—药物分析学]