The Methodology Study Of Specific Fibroblast Growth Factor Receptor1 (FGFR1) Inhibitor Design

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays crucial roles in cell proliferation, angiogenesis, migration, and survival. Aberration in FGFRs correlates with several malignancies such as bladder cancer, lung cancer and gastric cancer. FGFRs have proved to be attractive targets for therapeutic intervention in cancer. Computer-aided drug design (CADD) has contributed greatly in research and development of new drug and can be divided into structure-based drug design and ligand-based drug design.In this study, we studied the interaction between ligands and FGFR1 tyrosine kinase using structure-based and ligand-based computer-aided drug design (CADD) approaches, which has contributed greatly in research and development of new drug. In the second section, a combinatorial three-dimensional quantitative structure-activity relationship (3D-QSAR) was developed based on previous reported FGFR1 inhibitors with diverse structural skeletons. This model was proved to be effective by evaluating its performance on an external test set and a decoy dataset. Based on the combinatorial 3D-QSAR model, a virtual screening against SPECS database was performed, and nineteen novel active compounds were successfully identified, which showed higher than 50% inhibition rates against FGFR1 at 50μM compound concentration. In the third section, a target-specific scoring function was developed for FGFR1, and some novel FGFR1 inhibitors were successfully identified from the SPECS database, among which one compound presented inhibition activity at nM level. Then, a series of compounds with good activity and selectivity were synthesized through analyzing the structure-activity of crystal structures of complexes. In the fourth section, we summarized the key points of the full text and made an a outlook for the further work.