Citation: CHEN Zheng-Jun, JIANG Qing-Lin, HE Gu, HAN Bo, GUO Li. Multicomplex-Based Pharmacophore and QSAR of Aryl-Sulfamides as Pyruvate Kinase M2 Activators[J]. Acta Physico-Chimica Sinica, ;2013, 29(08): 1793-1803. doi: 10.3866/PKU.WHXB201305152 shu

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

CHEN Zheng-Jun ¹ ,
JIANG Qing-Lin ² ,
HE Gu ^1,3, ,
HAN Bo ⁴ ,
GUO Li ¹

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 Date: 11 March 2013
Available Online: 15 May 2013
Fund Project: 国家自然科学基金(30901837, 81001357, 81273471)资助项目 (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.
- Aryl-sulfamide derivative,
- Pyruvate kinase,
- Pharmacophore,
- Comparative molecular field analysis,
- Comparative molecular similarity indices analysis
1. [1]
  
  (1) Tennant, D. A.; Duran, R. V.; ttlieb, E. Nature Rev. Cancer2010, 10, 267. doi: 10.1038/nrc2817
2. [2]
  (2) Vander Heiden, M. G. Nature Rev. Drug Discov. 2011, 10, 671.doi: 10.1038/nrd3504
3. [3]
  (3) Cairns, R. A.; Harris, I. S.; Mak, T.W. Nature Rev. Cancer 2011,11, 85.
4. [4]
  (4) Levine, A. J.; Puzio-Kuter, A. M. Science 2010, 330, 1340.doi: 10.1126/science.1193494
5. [5]
  (5) Warburg, O. Science 1956, 123, 309. doi: 10.1126/science.123.3191.309
6. [6]
  (6) Vander Heiden, M. G.; Cantley, L. C.; Thompson, C. B. Science2009, 324, 1029. doi: 10.1126/science.1160809
7. [7]
  (7) Dang, C. V.; Kim, J.W.; Gao, P.; Yustein, J. Nat. Rev. Cancer2008, 8, 51. doi: 10.1038/nrc2274
8. [8]
  (8) Robey, R. B.; Hay, N. Semin. Cancer Biol. 2009, 19, 25.doi: 10.1016/j.semcancer.2008.11.010
9. [9]
  (9) Shaw, R. J. Curr. Opin. Cell Biol. 2006, 18, 598. doi: 10.1016/j.ceb.2006.10.005
10. [10]
  (10) Diaz-Ruiz, R.; Ri ulet, M.; Devin, A. Biochimica et Biophysica Acta-Bioenergetics 2011, 1807, 568. doi: 10.1016/j.bbabio.2010.08.010
11. [11]
  (11) Dombrauckas, J. D.; Santarsiero, B. D.; Mesecar, A. D.Biochemistry 2005, 44, 9417. doi: 10.1021/bi0474923
12. [12]
  (12) Takenaka, M.; Yamada, K.; Lu, T.; Kang, R.; Tanaka, T.;Noguchi, T. Eur. J. Biochem. 1996, 235, 366. doi: 10.1111/ejb.1996.235.issue-1-2
13. [13]
  (13) Christofk, H. R.; Vander Heiden, M. G.; Harris, M. H.;Ramanathan, A.; Gerszten, R. E.;Wei, R.; Fleming, M. D.;Schreiber, S. L.; Cantley, L. C. Nature 2008, 452, 230.doi: 10.1038/nature06734
14. [14]
  (14) Mao, J. Z.; Guo,W. H.; Shi, H. S.; Zhao, Y.W.; Yang, H. S.Journal of Sichuan University (Medical Science Edition) 2011,42, 308. [毛婧芝, 郭文浩, 石华山, 赵玉伟, 杨寒朔. 四川大学学报(医学版), 2011, 42, 308.]
15. [15]
  (15) Boxer, M. B.; Jiang, J. K.; Vander Heiden, M. G.; Shen, M.;Skoumbourdis, A. P.; Southall, N.; Veith, H.; Leister,W.;Austin, C. P.; Park, H.W.; Inglese, J.; Cantley, L. C.; Auld, D.S.; Thomas, C. J. J. Med. Chem. 2010, 53, 1048. doi: 10.1021/jm901577g
16. [16]
  (16) Thomas, C. J.; Boxer, M. B.; Jiang, J. K.; Vander Heiden, M. G.;Walsh, M. J.; Brimacombe, K.; Shen, M.; Skoumbourdis, A. P.;Park, H.W.; Cantley, L. C.; Auld, D. S. Abstr. Pap. Am. Chem. Soc. 2011, 242, 233-MEDI.
17. [17]
  (17) Anastasiou, D.; Poulogiannis, G.; Asara, J. M.; Boxer, M. B.;Jiang, J. K.; Shen, M.; Bellinger, G.; Sasaki, A. T.; Locasale, J.W.; Auld, D. S.; Thomas, C. J.; Vander Heiden, M. G.; Cantley,L. C. Science 2011, 334, 1278. doi: 10.1126/science.1211485
18. [18]
  (18) Anastasiou, D.; Yu, Y. M.; Israelsen,W. J.; Jiang, J. K.; Boxer,M. B.; Hong, B. S.; Tempel,W.; Dimov, S.; Shen, M.; Jha, A.;Yang, H.; Mattaini, K. R.; Metallo, C. M.; Fiske, B. P.; Courtney,K. D.; Malstrom, S.; Khan, T. M.; Kung, C.; Skoumbourdis, A.P.; Veith, H.; Southall, N.;Walsh, M. J.; Brimacombe, K. R.;Leister,W.; Lunt, S. Y.; Johnson, Z. R.; Yen, K. E.; Kunii, K.;Davidson, S. M.; Christofk, H. R.; Austin, C. P.; Inglese, J.;Harris, M. H.; Asara, J. M.; Stephanopoulos, G.; Salituro, F. G.;Jin, S. F.; Dang, L.; Auld, D. S.; Park, H.W.; Cantley, L. C.;Thomas, C. J.; Heiden, M. G. V. Nat. Chem. Biol. 2012, 8, 839.doi: 10.1038/nchembio.1060
19. [19]
  (19) Anastasiou, D.; Yu, Y. M.; Israelsen,W. J.; Jiang, J. K.; Boxer,M. B.; Hong, B. S.; Tempel,W.; Dimov, S.; Shen, M.; Jha, A.;Yang, H.; Mattaini, K. R.; Metallo, C. M.; Fiske, B. P.; Courtney,K. D.; Malstrom, S.; Khan, T. M.; Kung, C.; Skoumbourdis, A.P.; Veith, H.; Southall, N.;Walsh, M. J.; Brimacombe, K. R.;Leister,W.; Lunt, S.Y.; Johnson, Z. R.;Yen, K. E.; Kunii, K.;Davidson, S. M.; Christofk, H. R.; Austin, C. P.; Inglese, J.;Harris, M. H.; Asara, J. M.; Stephanopoulos, G.; Salituro, F. G.;Jin, S. F.; Dang, L. N.; Auld, D. S.; Park, H.W.; Cantley, L. C.;Thomas, C. J.; Vander Heiden, M. G. Nat. Chem. Biol. 2012, 8,1008.
20. [20]
  (20) Jiang, J. K.; Boxer, M. B.; Vander Heiden, M. G.; Shen, M.;Skoumbourdis, A. P.; Southall, N.; Veith, H.; Leister,W.;Austin, C. P.; Park, H.W.; Inglese, J.; Cantley, L. C.; Auld, D.S.; Thomas, C. J. Bioorganic & Medicinal Chemistry Letters2010, 20, 3387. doi: 10.1016/j.bmcl.2010.04.015
21. [21]
  (21) Walsh, M. J.; Brimacombe, K. R.; Veith, H.; Bougie, J. M.;Daniel, T.; Leister,W.; Cantley, L. C.; Israelsen,W. J.; VanderHeiden, M. G.; Shen, M.; Auld, D. S.; Thomas, C. J.; Boxer, M.B. Bioorganic & Medicinal Chemistry Letters 2011, 21, 6322.doi: 10.1016/j.bmcl.2011.08.114
22. [22]
  (22) Kubinyi, H. Drug Discov. Today 1997, 11, 457.
23. [23]
  (23) Kubinyi, H. Drug Discov. Today 1997, 12, 538.
24. [24]
  (24) SYBYL Molecular Modeling Software; Tripos Inc.: St. Louis,MO, USA, 2012.
25. [25]
  (25) http://www.rcsb.org
26. [26]
  (26) Discovery Studio, version 3.5; Accelrys Inc.: San Die , CA,USA, 2012.
27. [27]
  (27) Kang, C. M.; Zhao, X. H.;Wang, X. Y.; Cheng, J. G.; Lü, Y. T.Acta Phys. -Chim. Sin. 2013, 29, 431. [康从民, 赵绪浩, 王新宇, 程家高, 吕英涛. 物理化学学报, 2013, 29, 431.]doi: 10.3866/PKU.WHXB201211151
28. [28]
  (28) McIntosh, A. R.; Bookstein, F. L.; Haxby, J. V.; Grady, C. L.Neuroimage 1996, 3, 143. doi: 10.1006/nimg.1996.0016
29. [29]
  (29) Cramer, R. D. Perspect Drug Discov. Des. 1993, 1, 269.doi: 10.1007/BF02174528
30. [30]
  (30) Qiao, K.; Zeng, L. X.; Jin, H.W.; Liu, Z. M.; Zhang, L. R. Acta Phys. -Chim. Sin. 2012, 28, 1509. [乔康, 曾凌晓, 金宏威,刘振明, 张亮仁. 物理化学学报, 2012, 28, 1509.] doi: 10.3866/PKU.WHXB201203272
31. [31]
  (31) Tropsha, A.; lbraikh, A. J. Mol. Graph. Model. 2002, 20, 269.doi: 10.1016/S1093-3263(01)00123-1
32. [32]
  (32) Chaudhaery, S. S.; Roy, K. K.; Saxena, A. K. J. Chem Inf. Model. 2009, 49, 1590. doi: 10.1021/ci900049e
33. [33]
  (33) Ouyang, L.; He, G.; Huang,W.; Song, X. R.;Wu, F. B.; Xiang,M. L. Int. J. Mol. Sci. 2012, 13, 5348. doi: 10.3390/ijms13055348
34. [34]
  (34) He, G.; Qiu, M. H.; Li, R.; Ouyang, L.;Wu, F. B.; Song, X. R.;Cheng, L.; Xiang, M. L.; Yu, L. T. Chem. Biol. Drug Des. 2012,79, 960. doi: 10.1111/jpp.2012.79.issue-6
35. [35]
  (35) He, G.; Qiu, M. H.; Li, R.; Song, X. R.; Zheng, X.; Shi, J. Y.;Xu, G. B.; Han, J.; Yu, L. T.; Yang, S. Y.; Chen, L. J.;Wei, Y. Q.Molecular Simulation 2011, 37, 31. doi: 10.1080/08927022.2010.517529
36. [36]
  (36) Wu, F. B.; Xu, T.; He, G.; Ouyang, L.; Han, B.; Peng, C.; Song,X. R.; Xiang, M. L. Int. J. Mol. Sci. 2012, 13, 15668.doi: 10.3390/ijms131215668
37. [37]
  (37) Clark, M.; Cramer, R. D.; Jones, D. M.; Patterson, D. E.;Simeroth, P. E. Tetrahedron Comput. Method 1990, 3, 47.doi: 10.1016/0898-5529(90)90120-W
38. [38]
  (38) Dai, Z. J.; Zhou,W.; Yuan, Z. M. Acta Phys.-Chim. Sin. 2011,27, 1654. [代志军, 周玮, 袁哲明. 物理化学学报, 2011, 27,1654.] doi: 10.3866/PKU.WHXB20110735
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