Acta Phys. -Chim. Sin. ›› 2013, Vol. 29 ›› Issue (08): 1793-1803.doi: 10.3866/PKU.WHXB201305152

• BIOPHYSICAL CHEMISTRY • Previous Articles     Next Articles

Multicomplex-Based Pharmacophore and QSAR of Aryl-Sulfamides as Pyruvate Kinase M2 Activators

CHEN Zheng-Jun1, JIANG Qing-Lin2, HE Gu1,3, HAN Bo4, GUO Li1   

  1. 1 West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China;
    2 Department of Pharmacy, Chengdu Medical College, Chengdu 610500, P. R. China;
    3 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
    4 School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
  • Received:2013-03-11 Revised:2013-05-14 Published:2013-07-09
  • Contact: HE Gu
  • Supported by:

    The project was supported by the National Natural Science Foundation of China (30901837, 81001357, 81273471).


Pyruvate kinase M2 (PKM2) is well-known as a potential target for cancer therapy. In this study, the multicomplex-based pharmacophore (MCBP)-guided method was used to generate a comprehensive pharmacophore of PKM2 kinase based on a collection of crystal structures of PKM2- activator complex. This model was successfully used to identify the bioactive conformation and align 62 structurally diverse aryl-sulfamide derivatives. Quantitative structure-activity relationship (QSAR) analyses were performed on these PKM2 activators based on MCBP-guided alignment. With the comparative molecular field analysis (CoMFA) model, the cross-validated value (q2) was 0.545, and the non-crossvalidated value (r2) was 0.966. With the comparative molecular similarity indices analysis (CoMSIA) model, q2 and r2 were 0.653 and 0.987. These results may provide important information for further design of novel PKM2 activators.

Key words: Aryl-sulfamide derivative, Pyruvate kinase, Pharmacophore, Comparative molecular field analysis, Comparative molecular similarity indices analysis


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