Screening, Design And Activity Study Of Anti - Lung Cancer Drugs Targeted With Protein Tyrosine Kinase Family

Traditional drug discovery process is not only a time and money consuming process but also a randomness and blindness process. With the development of computer technology, bioinformatics, molecular biology and molecular pharmacology, computer aided drug design technology rise gradually, becoming an indispensable tool in modern drug discovery. Therefore, quantitative structure-activity relationship method and molecular docking technology were used to study three therapeutic targets(EGFR-T790 M, Met and Syk) of lung cancer and their inhibitors. This study can provide theoretical guidance for the development of lung cancer targeted drugs.Three-dimensional quantitative structure-activity relationship method was carried out to explore the 55 quinazoline analogues of EGFR-T790 M inhibitor. A optimum model was built that exhibited statistically significant results: Q2 =0.651, R2=0.988 and the structural features that may affect the EGFR-T790 M inhibitory activities were obtained. According to these features, a series of compounds which have EGFR-T790 M inhibitory activities were designed, and the activity values of these compounds were predicted.Three-dimensional quantitative structure-activity relationship method and molecular docking technology were used to research 58 Met kinase inhibitors. A optimum model was built that exhibited statistically significant results: Q2 =0.709, R2=0.994. The structural features that may affect the Met inhibitory activities and the action mode between the drug molecules and Met protein kinase were got.Based on structures and activities of 44 potential Syk kinase inhibitors, we used three-dimensional quantitative structure-activity relationship method to get a optimum model(Q2 =0.648, R2=0.857) and the relationship between structure and inhibitory activities was obtained. Then, molecular docking technology was carried out to explore the action mode between the inhibitors and Syk protein kinase. According to these results, we screened and designed new potential Syk kinase inhibitors.In this paper, we used three-dimensional quantitative structure-activity relationship method to get three models(Co MFA model for EGFR-T790 M inhibitors, Co MSIA model for Met inhibitors and Co MSIA model for Syk inhibitors). The internal and external validation method was used to proved that these three models have high reliability and stability. These three models can provide theoretical foundation for designing a new type of EGFR-T790 M, Met and Syk targeted drugs of lung cancer. At the same time, the molecular docking technology was used to explore the binding mode between Met kinase, Syk kinase and their inhibitors. These can provide theoretical guidance for screening Met and Syk targeted drugs of lung cancer.