3D-QSAR And Molecular Docking Studies On Imidazopyridazines As Kinase Inhibitors

Computer-aided drug design(CADD)correlates molecular structure features to their bioactivity,studies the interaction modes between the biomacromolecules and their micromolecules,investigates rapidly and accurately the key structural features affecting activity based on the model building,guides structural modification and activity prediction of lead and to aid the design and synthesis of highly effective leads targeted enzyme.In Chapter 1,a brief introduction of the computer-aided drug design method was given,as well as 3D-QSAR,the validation of QSAR models,virtual screening,molecular docking.In Chapter 2,41 VEGFR2 inhibitors(30 compounds in training set and 11 in test set)were subjected to 3D-QSAR study using topomer CoMFA.Four kinds of fragment splitting modes were practiced to build consensus models and the developed models were assessed by the external test set validation.Four topomer CoMFA models have similar statistical results and topomer CoMFA model 2 showed better stability and external predictive ability.Further explanation of the three-dimensional contour map can describe the relationship between the structure and activity of the molecules and provide a theoretical basis for molecular design and activity prediction of VEGFR2 inhibitors in future.In Chapter 3,the imidazo[1,2-b]pyridazine of the compound No.1 with the highest activity was chosen as the common core,and its remaining RN-group acted as queries to screen ZINC database for similar fragments by using Topomer Search technology.The obtained R1 and R2 fragments were added to the common core respectively.Finally 68 new imidazo[1,2-b]pyridazine compounds were designed and the potential activities were predicted by topomer CoMFA model 2.Further the binding modes were studied by using Surflex-dock.The docking results showed good hydrogen bond interactions of the designed compounds with targeted protein VEGFR2,thus the rationality of this design was verified from the perspective of kinase-inhibitor complex.