| PI3Kαwas the primary phosphoinositide 3-kinases(PI3Ks)isoform,which was an important regulator of the PI3K/AKT/m TOR pathways.The aberrant activation of PI3Kαwas involved in oncogenic RTK signaling and tumorigenesis.The research work of this paper was mainly described from the following parts:1.Based on 65 3-phenylsulfonylaminopyridine derivatives,3D-QSAR model was generated(Co MFA:q~2=0.704,r~2=0.994;Co MSIA:q~2=0.804,r~2=0.996).According to the structure-activity relationship revealed by 3D-QSAR model,5PI3Kαinhibitors were designed with potent inhibitory activity against PI3Kα.Molecular docking and molecular dynamics simulation were carried out to analyze the binding mode between PI3Kαand drug.2.Based on 85 difluoromethylbenzimidazole derivatives,3D-QSAR model was generated(Co MFA:q~2=0.797,r~2=0.996;Co MSIA:q~2=0.567,r~2=0.960).According to the structure-activity relationship revealed by 3D-QSAR model,2PI3Kαinhibitors were designed and synthesized,which showed effective PI3Kαinhibitory activity.Molecular docking and molecular dynamics simulation were carried out to analyze the binding mode between PI3Kαand drug.Inconclusion,3-phenylsulfonamidopyridinederivativesand difluoromethylbenzimidazole derivatives were studied by 3D-QSAR,molecular docking and molecular dynamics.Two compounds were designed and synthesized,which can effectively inhibit PI3Kα.It provided certain guidance for the design of PI3Kαinhibitors. |
