A Three Dimensional Pharmacophore Modeling for KDR and Tie-2 Receptor Tyrosine Kinase Inhibitors and Virtual Screening for New Multikinase Inhibitors

摘要

The fundamental role that receptor tyrosine kinases play in cancer and other proliferative diseases has provided the impetus for an extensive effort to develop multikinase inhibitors. In this study three dimensional Pharmacophore models were developed using recently synthesized KDR and Tie-2 receptor tyrosine kinase inhibitors by using CATALYST HypoGen program. The high cost difference (68.098 for KDR and 46.971 for Tie-2), good correlation coefficient (0.948 for KDR and 0.963 for Tie-2) and low root mean square deviation (0.871 for KDR and 0.668 for Tie-2) suggest that highly predictive pharmacophore models were successfully obtained. The models were further validated by two methods, first by using test set compounds (305 for KDR and 131 for Tie-2) which resulted a correlation of 0.606 for KDR and 0.706 for Tie-2 between HypoGen estimated activities vs. experimental activities and secondly by fischer randomization test. The application of the validated pharmacophore models shows great success in screening in-house database and predicted 61compounds with multikinase activity.