Insight Into The Selective Mechanisms Of ZSTK474 And Its Analogs Binding With PI3K By Using Molecular Simulation Methods

Cancer is the second leading cause of death in the world.In recent years,protein targeted anti-cancer drugs have developed rapidly,and some drugs that can directly act on target proteins regulating tumor cell growth and proliferation have been marketed for clinical use while the drugs of inhibiting one or more proteins in a specific cell transduction pathway to regulate cell transduction can produce a more significant anti-tumor effect than inhibiting a single tumor-associated protein.Research have confirmed that the PI3k/AKT/mTOR signaling pathway is one of the key signaling pathways that regulate the metabolism of tumor cells.Phosphatidylinositol 3-kinase,the PI3K pathway,is one of the key signal transduction systems that link oncogenes and multiple receptor classes to essential cellular functions and is a common signaling pathway in human cancers.It integrates signals from growth factors,cytokines and other environmental signals,and transforms them into intracellular signals that regulate multiple signaling pathways.These pathways control many physiological functions and cellular processes,including cell proliferation,growth,survival and metabolism.Activation of PI3K is frequently found in a variety of cancers and is well suited for drug intervention,making it the most attractive drug target and providing an excellent opportunity for cancer treatment.Recent preclinical studies have demonstrated that different PI3K subtypes play different roles in cell signaling and cancer,suggesting that by inhibiting the PI3K pathway,multiple cancers can be effectively controlled by selectively inhibiting different subtypes.The first part briefly introduces the relationship between cancer and PI3K family proteins,including the type of PI3K protein,the change of PI3K subtype in cancer,the small molecule inhibitors and their analogues used in the current study.The second part introduces the molecular simulation methods and corresponding theoretical basis.The third part uses molecular dynamics?MD?simulation to study the binding mode between ZSTK474 and its analogs and PI3K?,and to explore the selective mechanism of these small molecules on PI3K?.The key structural features associated with PI3Kbeta inhibitory activity were discovered.The simulation results show that MET773,TRP781,ILE797,ILE845,ILE930 and ASP931 are key residues in all five ligands/protein systems with high or low activity.When the 4-position group is a larger group or a group capable of forming a hydrogen bond such as-CONHMe and-OBu,the ligand will cause low activity or even inactivity.The 2-position of benzimidazole should be an electron withdrawing group such as-CHF₂ or a shorter electron donating group,and a too short hydrogen bond donor may form a hydrogen bond with the amino acid residue on the side of the pocket to prevent small molecule binding into the pocket.In part four,the molecular dynamics simulation method was used to study the binding mode between ZSTK474 or its analogues and PI3K?,and to explore the selective mechanism of these compounds on PI3K?.The results show that although the PI3K family proteins are highly conserved,different ligand/protein systems have different selective mechanisms.In this thesis,molecular dynamics simulation and free energy methods were used to study the interaction mechanisms between PI3K protein inhibitor ZSTK474 and its analogues and different PI3K family proteins at the molecular level,and to explore the selective mechanism.The results provide a theoretical basis for the design and screening of selective PI3K inhibitor.