Three-dimensional Quantitative Structure-activity Relationship Analyses And Molecular Docking Study For Activin Receptor-like Kinase Inhibitors

Computer-aided drug design(CADD)can improve the hit rate of new drug molecules compared to traditional HTS and combinatorial chemistry.It not only explains the therapeutic activity of the drug on the basis of molecules,but also predicts new derivatives that can improve biological activity.In the process of drug discovery,CADD is mainly used in three aspects:(1)filtering large database of compounds into a collection of a few active compounds that can be tested experimentally;(2)directing the optimization of lead compounds,increasing their affinity or optimizing drug metabolism and pharmacokinetic properties,including absorption,distribution,metabolism,excretion and potential toxicity(ADMET);(3)design of new compounds,through the "molecular growth method" or"fragment splicing method" to design a new chemical type.This paper was divided into four chapters:The first chapter was divided into two parts.The first part briefly summarized the basic development route of drug discovery and molecular simulation.The second part introduced in detail the relationship between transforming growth factor superfamily and activin receptor-like kinase,and their biology mechanism.The second chapter focuses on the research methodology,mainly analyzed the principle and method of the quantitative structure-activity relationship and molecular docking,and briefly introduced the research route of this study.In the third chapter,the protein crystal structure of ALK4 and ALK7 were constructed by homology modeling method.The mechanism and difference of interaction about EW-7197 and Galunisertib with ALK5 were analyzed by molecular docking method.EW-7197 was interacted with 7 subtypes of activin receptor-like kinase,and the interaction pattern and mechanism of EW-7197 were analyzed,and it's selectivity to ALK5 was further verified.In the fourth chapter,a series of imidazole ALK5 inhibitors with the same parent nucleus as EW-7197 were subjected to molecular docking and 3D-QSAR study.The CoMFA and CoMSIA models were constructed with 61 compounds simultaneously,and the relationship between potential energy map and molecular activity was analyzed by using the dominant conformation of EW-7197 and ALK5 as template molecules.Not only laid a theoretical foundation for the design of novel high selectivity,high activity,high safety and low toxicity and side effects,and reduced the workload of actual screening,but also given great hope for the TGF-?/activin pathway inhibitors in clinical treatment.