BCR-ABL tyrosine kinase inhibitor pharmacophore model derived from a series of phenylaminopyrimidine-based (PAP) derivatives |
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Authors: | Jing Cui Rao Fu Li-Hua Zhou Sheng-Ping Chen Guang-Wu Li Shen-Xian Qian Shu Liu |
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Institution: | 1. Institute of Neurobiology, Anhui Medical University, Meishan Road 81, Hefei 230032, China;2. Department of Hematology, The First People’s Hospital of Hangzhou, No. 261 Huansha Road, Hangzhou 310006, China;3. Department of Anatomy, Zhong Shan School of Medicine, Sun Yat-Sen University, No. 74 Zhongshan 2nd Road, Guangzhou 510080, China |
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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 Q2 = 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. |
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