2. Academic Validation
  3. Integrating docking scores, interaction profiles and molecular descriptors to improve the accuracy of molecular docking: toward the discovery of novel Akt1 inhibitors

Integrating docking scores, interaction profiles and molecular descriptors to improve the accuracy of molecular docking: toward the discovery of novel Akt1 inhibitors

  • Eur J Med Chem. 2014 Mar 21:75:11-20. doi: 10.1016/j.ejmech.2014.01.019.
Wenhu Zhan 1,  Daqiang Li 1,  Jinxin Che 1,  Liangren Zhang 2,  Bo Yang 3,  Yongzhou Hu 1,  Tao Liu 4,  Xiaowu Dong 5
Affiliations

Affiliations

  • 1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083, China.
  • 3 Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
  • 4 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: lt601@zju.edu.cn.
  • 5 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: dongxw@zju.edu.cn.
PMID: 24508830 DOI: 10.1016/j.ejmech.2014.01.019
Abstract

A set of forty-seven Akt1 inhibitors was used for the development of molecular docking based QSAR model by using nonlinear regression. The integration of docking scores, key interaction profiles and molecular descriptors remarkably improved the accuracy of the QSAR models, providing reasonable statistical parameters (Rtrain(2) = 0.948, Rtest(2) = 0.907 and Qcv(2) = 0.794). The established MD-SVR model based structural modification of new 4-amino-pyrimidine derivatives was further performed, and six compounds 56a,b and 60a-d with good prediction activities were synthesized and biologically evaluated. All of these compounds exhibited promising Akt1 inhibitory and antiproliferative activities, suggesting the reliability and good application value of the established MD-SVR model in the development of Akt1 inhibitors.

Keywords

Akt1 inhibitors; Antiproliferative activity; Molecular docking; Support vector regression (SVR); Synthesis.

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