3D-QSAR and Docking Studies on Pyrimidine Derivatives of Second-Generation ALK Inhibitors

Abstract Anaplastic lymphoma kinase (ALK) is a promising target for the treatment of non-small cell lung cancer. Under crizotinib treatment, drug resistance and progressive disease appeared after point mutations arising in domain ALK. Second-generation ALK inhibitors can solve deficiencies first generation, especially cancer chemotherapy. Ceritinib (LDK378), pyrimidine derivative, example, inhibit activity with an IC50 value 40.7 nmol/L, experience progression initial crizotinib. Unfortunately, clear structure–activity relationships have not been identified to date, impeding rational design future compounds possessing inhibition activity. To explore interesting insights into structures derivatives that influence activities second-generation inhibitors, three-dimensional quantitative relationship (3D-QSAR) molecular docking were performed on total 45 pyrimidine. Comparative field analysis (CoMFA) comparative similarity index (CoMSIA) techniques used generate 3D-QSAR models. CoMFA CoMSIA using Sybyl X 2.0 package. Molecular was Surflex-Dock module SYBYL-X We found model non-cross-validated r2 0.998, cross-validated q 2 0.663, F statistic 2,401.970, while 0.988; 0.730, 542.933 models, suggesting good predictability 3D contour maps results suggested different groups core parts could enhance biological activities. Based these results, established models binding obtained favor prediction new will be helpful reasonable future.