BCR-ABL tyrosine kinase inhibitor pharmacophore model derived from a series of phenylaminopyrimidine-based (PAP) derivatives

Jing Cui; Rao Fu; Li-Hua Zhou; Sheng-Ping Chen; Guang-Wu Li; Shen-Xian Qian; Shu Liu

doi:10.1016/j.bmcl.2013.01.113

BCR-ABL tyrosine kinase inhibitor pharmacophore model derived from a series of phenylaminopyrimidine-based (PAP) derivatives

Bioorg Med Chem Lett. 2013 Apr 15;23(8):2442-50. doi: 10.1016/j.bmcl.2013.01.113. Epub 2013 Feb 9.

Authors

Jing Cui¹, Rao Fu, Li-Hua Zhou, Sheng-Ping Chen, Guang-Wu Li, Shen-Xian Qian, Shu Liu

Affiliation

¹ Department of Hematology, The First People's Hospital of Hangzhou, No 261 Huansha Road, Hangzhou 310006, China.

PMID: 23473682
DOI: 10.1016/j.bmcl.2013.01.113

Abstract

To reveal novel insights into the inhibition of BCR-ABL tyrosine kinase, pharmacophore mapping studies were performed for a series of phenylaminopyrimidine-based (PAP) derivatives, including imatinib (Gleevec). A seven-point pharmacophore model with one hydrophobic group (H), two hydrogen bond donors (D) and four aromatic rings (R) was developed using phase (pharmacophore alignment & scoring engine). The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of 0.886 and a survival score of 4.97 for training set molecules. The model showed excellent predictive power, with a correlation coefficient of Q(2)=0.768 for an external test set of ten molecules. The results obtained from our studies provide a valuable tool for designing new lead molecules with potent activity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Design
Fusion Proteins, bcr-abl / antagonists & inhibitors*
Models, Molecular
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemistry*
Pyrimidines / pharmacology*
Quantitative Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrimidines
Fusion Proteins, bcr-abl