Molecular Simulation Study On The Mechanism Of PI3K Selective Inhibitor

PI3K/Akt/mTOR signaling pathway is a very important cell signal transduction pathway that regulates many important physiological functions,such as cell growth,proliferation,differentiation,migration,angiogenesis,and glucose metabolism.Among them,phosphatidylinositol-3-kinase(PI3K)is a key intracellular signal transduction molecule in this pathway.And its signal imbalance can induce a variety of diseases,so PI3K has become a very promising drug target.According to the different structure,PI3K can be divided into type I,type II and type III.In this paper,only type I PI3K was studied,Type ⅠPI3K includes four isoforms of α,β,δ and y:PI3Ka is mainly related to the formation of multiple solid tumors;moreover,PI3Kβ is mainly related to thrombosis and tumor;PI3Kδ and PI3Kγ are mainly related to inflammation and autoimmune diseases.According to the relevant reports of multiple inhibitors entering clinical trials,it can be found that non-selective inhibitors have some problems such as poor targeting,poor tolerability and many adverse reactions(mainly hypertension,thrombocytopenia,lower respiratory tract infection)during use.Therefore,increasing the selectivity of inhibitors can improve the drug tolerance and targeting and reduce the adverse drug reactions.Due to the widespread low selectivity of PI3K inhibitors,the high selection of PI3K inhibitors has become an important and difficult point in research and development.Aiming at the selective mechanism of inhibitors,this paper used the methods of molecular docking and molecular dynamics to analyze the action mechanim and selective mechanism of different skeletal PI3K inhibitors and different isoforms and to explore the reasons for the differences in inhibitor selectivity.It hopes that this study can provide a theoretical basis for the design of highly selective PI3K inhibitors.(1)Molecular simulation study on the selective mechanism of PI3Kβinhibitors in the α and β isoformsIn this chapter,selects four representative compounds of quinazoline PI3Kβ inhibitors with obvious selectivity and different activities to a and βisoforms,and use molecular docking and molecular dynamics methods to explore the structure-activity relationship and the action mechanism between inhibitors and PI3Kα or PI3Kβ proteins.Furthermore,the selective mechanism of inhibitors among a and β isoforms were analyzed,which provided some theoretical reference values for the design of the highly selective PI3Kβ inhibitors.The experimental results show that the inhibitors have less interaction in PI3Ka except hydrophobic interaction,which may be the reason for the poor activity.The inhibitors can occupy the hydrophobic region of the binding pocket better in PI3Kβ protein,and can form stable hydrogen bond interaction with key residues Va1882,Lys833 and Met804.It is speculated that the above idea is the reason why the inhibitor has better selectivity in the β isoform.(2)Molecular simulation study on the selective mechanism of PI3Kδinhibitors in the a and δ isoformsIn this chapter,selects four representative compounds of 4,6,7,8-tetrahydropyrido-[4,3-d]-pyrimidine PI3Kδ inhibitors and use molecular docking and molecular dynamics methods to explore the structure-activity relationship and the action mechanism between inhibitors and PI3Kα or PI3Kδ proteins.Furthermore,the selective mechanism of inhibitors among α and δ isoforms were analyzed,which provided some theoretical reference values for the design of highly selective PI3Kδ inhibitors.The experimental results show that van der Waals force,hydrogen bonding and electrostatic interaction all play important roles in the binding of inhibitors to PI3Kα and PI3Kδ,but compared with PI3Kα protein,PI3Kδ protein can form hydrogen bonds with key residues Va1828,Lys779,and Met752,and the hydrophobic interaction is stronger.It is speculated that the above conclusion is the reason why the inhibitor has better selectivity for the δ isoform.(3)Molecular simulation of the selective mechanism of PI3Kγinhibitors in β and γ isoformsIn this chapter,select four representative compounds of azaisoindolone PI3Ky inhibitors,and use molecular docking and molecular dynamics methods to explore the structure-activity relationship and the action mechanism between inhibitors and PI3Kβ or PI3Kγ proteins.Furthermore,the selective mechanism of inhibitors among β and γisoforms were analyzed,which provided some theoretical reference value for the design of highly selective PI3Ky inhibitors.The experimental results show that van der Waals force,hydrogen bonding and electrostatic interaction all play important roles in the binding of inhibitors to PI3Kβand PI3Kγ.The inhibitors can bind to the hinge residue Va1882 in both proteins,but the inhibitors can stably bind to the key residue Lys833 in PI3Kγ protein.It is speculated that the above viewpoint is the reason why the inhibitor has better selectivity for the y isoform.