Computer-aided Study On The Binding Mechanism Of CDK4/6 Inhibitor

With the advancement of science and technology and the rapid economic development,the products of the chemical industry have gradually began to transform,from the initial mass production of basic chemicals to high-profit product engineering,such as the production of pharmaceuticals.However,in the drug production process,we often need to invest a lot of labor and capital,and the research and development process is very slow.With the development of Internet technology,we can improve the efficiency of drug research and development through computer-aided drug design methods,that is,with the help of computer simulation and calculation of the interaction mode between small drug molecules and the target protein of the human body,to design lead compounds and optimization.Cyclin-dependent kinase 4/6（CDK4/6）is a specific serine/threonine kinase and is also an important target for the treatment of breast cancer and other cancers.Therefore,the development of new and efficient CDK4/6 inhibitors as soon as possible is the key to the treatment of breast cancer and other cancers.In this study,the interaction between 85 inhibitor molecules and CDK4/6 receptor was investigated by using three-dimensional quantitative structure-activity relationship（3D-QSAR）and molecular docking.For the CDK4 receptor,we successfully established a satisfactory CoMSIA model(Q²=0.600,R²_ncv=0.986,F=371.728,R²_pre=0.952).From the point of view of the contribution rate of each force field,hydrogen bonding is the most important factor affecting the activity of inhibitor molecules,followed by electrostatic interaction,while hydrophobic interaction and steric hindrance are relatively small.For the CDK6 receptor,the statistical parameter models of CoMSIA were Q²=0.536,R²_ncv=0.991,SEE=0.078 and F=564.38.Among them,the contribution rate of the hydrogen bond donor and acceptor field is as high as 39.1%;the contribution rate of the electrostatic field is slightly second,at 30.5%;the contribution rate of the hydrophobic field and the steric field are 20.7%and 9.7%,respectively.The docking simulation results show that these inhibitor molecules bind tightly with CDK4/6 at the ATP site.This conformation is mainly composed of hydrogen bonding,static electricity,hydrophobicity,andπcations to help the inhibitor molecule and the receptor bind stably.This study reveals the relationship between the structural features and inhibitory activity of CDK4/6 inhibitors,as well as the binding mode between small ligand molecules and CDK4/6 receptors,which will provide guidance for the design and optimization of new CDK4/6 inhibitors in the future.