title: Theoretical Studies on Pyrazolo[3,4-d]pyrimidine Derivatives as Potent Dual c-Src/Abl Inhibitors Using 3D-QSAR and Docking Approaches.
abstract: In recent years, the development of dual or multi-targeted inhibitors has captured extensive attention of research for treating of malignancies. In this paper, three-dimensional quantitative structure-activity relationship and docking studies were performed on 87 pyrazolo[3,4-d]pyrimidines as dual Src/Abl inhibitors. The appropriate binding orientations and conformations of these compounds interacting with both Src and Abl kinases were revealed by docking studies, and the established optimum CoMFA models yielded q(2) =0.856, R(2) =0.966 for Src and q(2) =0.869, R(2) =0.974 for Abl, and the best CoMSIA models gave q(2) =0.877, R(2) =0.979 for Src and q(2) =0.885, R(2) =0.982 for Abl. Systemic external validations further confirm the satisfactory predictive power of these models, producing R(2) pred values of 0.872 and 0.865 for Src, 0.876 and 0.867 for Abl, r(2) m values of 0.832 and 0.928 for Src, 0.838 and 0.904 for Abl, respectively. In addition, through a comparison between 3D-QSAR contour maps and docking results, it is revealed that the hydrophobic and electrostatic interactions of compounds play significant roles for the inhibitory activity against both Src and Abl kinases. Some structural factors influencing the activities of these compounds were discussed in detail. The key amino acids impacting the receptor-ligand interactions have been identified. These theoretical results can offer useful references for designing novel potential dual Src/Abl inhibitors.
authors.affiliation: Department of Physical Chemistry, College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China tel: +86 20 39352119, fax: +86 20 84112245.
authors.forename: Guo Hua
authors.initials: GH
authors.lastname: Zeng
authors.affiliation: Department of Cardiothoracic Surgery, Affiliated Second Hospital of Guangzhou Medical University, Guangzhou 510260, P. R. China.
authors.forename: Dan Qing
authors.initials: DQ
authors.lastname: Fang
authors.affiliation: Department of Physical Chemistry, College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China tel: +86 20 39352119, fax: +86 20 84112245. wuwenjuan83@126.com.
authors.forename: Wen Juan
authors.initials: WJ
authors.lastname: Wu
authors.affiliation: Department of Physical Chemistry, College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China tel: +86 20 39352119, fax: +86 20 84112245.
authors.forename: Ju Ping
authors.initials: JP
authors.lastname: Wang
authors.affiliation: Department of Physical Chemistry, College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China tel: +86 20 39352119, fax: +86 20 84112245.
authors.forename: Wen Guo
authors.initials: WG
authors.lastname: Xie
authors.affiliation: Department of Physical Chemistry, College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China tel: +86 20 39352119, fax: +86 20 84112245.
authors.forename: Shao Jie
authors.initials: SJ
authors.lastname: Ma
authors.affiliation: School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R.China.
authors.forename: Jing Heng
authors.initials: JH
authors.lastname: Wu
authors.affiliation: School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R.China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Shen
keywords: 3D-QSAR; Abl; Docking⋅Src; Pyrazolo[3,4-d]pyrimidine derivatives