Display options
Cite
Liu L, Ma Y, Wang RL, et al. Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics. Drug Des Devel Ther. 2013;7:279-88doi: 10.2147/DDDT.S42113.
Liu, L., Ma, Y., Wang, R. L., Xu, W. R., Wang, S. Q., & Chou, K. C. (2013). Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics. Drug design, development and therapy, 7279-88. https://doi.org/10.2147/DDDT.S42113
Liu, Lei, et al. "Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics." Drug design, development and therapy vol. 7 (2013): 279-88. doi: https://doi.org/10.2147/DDDT.S42113
Liu L, Ma Y, Wang RL, Xu WR, Wang SQ, Chou KC. Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics. Drug Des Devel Ther. 2013 Apr 08;7:279-88. doi: 10.2147/DDDT.S42113. Print 2013. PMID: 23630413; PMCID: PMC3623550.
Copy Download .nbib Format: NLM
Share it on

Drug Des Devel Ther. 2013 Apr 08;7:279-88. doi: 10.2147/DDDT.S42113. Print 2013.

Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics.

Drug design, development and therapy

Lei Liu, Ying Ma, Run-Ling Wang, Wei-Ren Xu, Shu-Qing Wang, Kuo-Chen Chou

Affiliations

  1. PET/CT Center, General Hospital of Tianjin Medical University, Tianjin, People's Republic of China.

PMID: 23630413 PMCID: PMC3623550 DOI: 10.2147/DDDT.S42113

Abstract

The high prevalence of type 2 diabetes mellitus in the world as well as the increasing reports about the adverse side effects of the existing diabetes treatment drugs have made developing new and effective drugs against the disease a very high priority. In this study, we report ten novel compounds found by targeting peroxisome proliferator-activated receptors (PPARs) using virtual screening and core hopping approaches. PPARs have drawn increasing attention for developing novel drugs to treat diabetes due to their unique functions in regulating glucose, lipid, and cholesterol metabolism. The reported compounds are featured with dual functions, and hence belong to the category of dual agonists. Compared with the single PPAR agonists, the dual PPAR agonists, formed by combining the lipid benefit of PPARα agonists (such as fibrates) and the glycemic advantages of the PPARγ agonists (such as thiazolidinediones), are much more powerful in treating diabetes because they can enhance metabolic effects while minimizing the side effects. This was observed in the studies on molecular dynamics simulations, as well as on absorption, distribution, metabolism, and excretion, that these novel dual agonists not only possessed the same function as ragaglitazar (an investigational drug developed by Novo Nordisk for treating type 2 diabetes) did in activating PPARα and PPARγ, but they also had more favorable conformation for binding to the two receptors. Moreover, the residues involved in forming the binding pockets of PPARα and PPARγ among the top ten compounds are explicitly presented, and this will be very useful for the in-depth conduction of mutagenesis experiments. It is anticipated that the ten compounds may become potential drug candidates, or at the very least, the findings reported here may stimulate new strategies or provide useful insights for designing new and more powerful dual-agonist drugs for treating type 2 diabetes.

Keywords: ADME; PPAR-alpha; PPAR-gamma; binding pocket; core hopping; diabetes; dual-agonist drug; molecular docking

References

  1. Annu Rev Med. 2002;53:409-35 - PubMed
  2. Biochemistry. 1999 Sep 14;38(37):11905-13 - PubMed
  3. J Comput Aided Mol Des. 2007 Oct-Nov;21(10-11):575-90 - PubMed
  4. Med Chem. 2011 Mar;7(2):121-6 - PubMed
  5. Nature. 2008 Jan 31;451(7178):591-5 - PubMed
  6. Protein Pept Lett. 2011 May;18(5):440-9 - PubMed
  7. Diabetes Care. 2004 May;27(5):1047-53 - PubMed
  8. PLoS One. 2011 Apr 11;6(4):e18414 - PubMed
  9. Curr Med Chem. 2004 Aug;11(16):2105-34 - PubMed
  10. Biochem Biophys Res Commun. 1999 Jun 7;259(2):420-8 - PubMed
  11. J Theor Biol. 2008 Sep 21;254(2):294-300 - PubMed
  12. Eur Biophys J. 2005 Jun;34(4):273-84 - PubMed
  13. Biophys J. 1984 May;45(5):881-9 - PubMed
  14. Bioorg Med Chem Lett. 2000 Jun 5;10(11):1155-8 - PubMed
  15. J Biol Chem. 2001 Oct 12;276(41):37731-4 - PubMed
  16. Biopolymers. 1988 Nov;27(11):1795-815 - PubMed
  17. Protein Eng Des Sel. 2009 Jun;22(6):349-55 - PubMed
  18. Trends Pharmacol Sci. 2005 May;26(5):244-51 - PubMed
  19. Br J Pharmacol. 2003 Oct;140(3):527-37 - PubMed
  20. PLoS One. 2011;6(11):e28111 - PubMed
  21. J Biol Chem. 1995 Jun 2;270(22):12953-6 - PubMed
  22. Pharm Res. 2004 Sep;21(9):1531-8 - PubMed
  23. Proc Natl Acad Sci U S A. 2009 May 5;106(18):7379-84 - PubMed
  24. PLoS One. 2011;6(8):e23505 - PubMed
  25. Protein Pept Lett. 2011 Oct;18(10):1021-7 - PubMed
  26. Protein Eng Des Sel. 2009 Nov;22(11):699-705 - PubMed
  27. Bioorg Med Chem. 2008 Aug 15;16(16):7770-6 - PubMed
  28. J Clin Pharmacol. 2003 Nov;43(11):1244-56 - PubMed
  29. Biochem Biophys Res Commun. 2008 Nov 14;376(2):321-5 - PubMed
  30. Biochem Biophys Res Commun. 2008 Dec 26;377(4):1243-7 - PubMed
  31. Br J Pharmacol. 2005 Feb;144(3):308-16 - PubMed
  32. Acta Pharmacol Sin. 2007 May;28(5):634-42 - PubMed
  33. PLoS One. 2011 Mar 30;6(3):e18258 - PubMed
  34. Acta Crystallogr D Biol Crystallogr. 2004 Aug;60(Pt 8):1355-63 - PubMed
  35. Bioorg Med Chem. 2009 Jan 15;17(2):569-75 - PubMed
  36. J Med Chem. 2002 Jan 3;45(1):137-42 - PubMed
  37. Biochim Biophys Acta. 2001 Mar 30;1531(1-2):68-76 - PubMed
  38. Biopolymers. 1987 Feb;26(2):285-95 - PubMed
  39. Mol Biosyst. 2012 Feb;8(2):629-41 - PubMed
  40. Anal Biochem. 1996 Jan 1;233(1):1-14 - PubMed
  41. Biochem Biophys Res Commun. 2004 Jun 25;319(2):433-8 - PubMed
  42. Biophys Chem. 1984 Aug;20(1-2):61-71 - PubMed
  43. Neural Netw. 2004 Jan;17(1):65-71 - PubMed
  44. J Comput Aided Mol Des. 1997 Sep;11(5):425-45 - PubMed
  45. J Clin Invest. 2006 Mar;116(3):581-9 - PubMed
  46. J Comput Chem. 2009 Jan 30;30(2):295-304 - PubMed
  47. Mol Pharm. 2011 Jun 6;8(3):841-51 - PubMed
  48. Drugs. 2000 Jul;60(1):95-113 - PubMed
  49. J Med Chem. 2002 Dec 5;45(25):5492-505 - PubMed
  50. J Biol Chem. 2005 May 6;280(18):17880-90 - PubMed
  51. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13919-24 - PubMed
  52. J Chem Inf Comput Sci. 2004 May-Jun;44(3):1111-22 - PubMed
  53. J Med Chem. 2003 Apr 10;46(8):1306-17 - PubMed
  54. J Chem Theory Comput. 2009 Sep 8;5(9):2322 - PubMed
  55. J Chem Inf Model. 2005 Jan-Feb;45(1):177-82 - PubMed
  56. Acta Crystallogr D Biol Crystallogr. 2002 Jun;58(Pt 6 No 1):899-907 - PubMed
  57. Bioorg Med Chem. 2008 Jun 1;16(11):5871-80 - PubMed
  58. Biopolymers. 1994 Jan;34(1):143-53 - PubMed
  59. Trends Biochem Sci. 1989 Jun;14(6):212-3 - PubMed
  60. Expert Opin Ther Pat. 2010 Dec;20(12):1627-51 - PubMed
  61. Eur J Drug Metab Pharmacokinet. 2007 Jan-Mar;32(1):29-37 - PubMed
  62. J Biol Chem. 1999 Feb 26;274(9):5474-82 - PubMed
  63. J Proteome Res. 2004 Nov-Dec;3(6):1284-8 - PubMed
  64. J Med Chem. 2004 Aug 12;47(17):4118-27 - PubMed
  65. Mol Biosyst. 2011 Mar;7(3):911-9 - PubMed
  66. PLoS One. 2012;7(1):e31048 - PubMed
  67. Nat Rev Drug Discov. 2002 Jul;1(7):551-5 - PubMed
  68. Faraday Discuss. 1998;(111):201-8; discussion 225-46 - PubMed
  69. Med Clin North Am. 2004 Jul;88(4):787-835, ix - PubMed
  70. Mol Pharmacol. 2007 Feb;71(2):398-406 - PubMed
  71. PLoS One. 2012;7(6):e38546 - PubMed
  72. Toxicol Sci. 2007 Nov;100(1):248-58 - PubMed
  73. J Med Chem. 2002 Feb 14;45(4):789-804 - PubMed
  74. J Comput Chem. 2005 Dec;26(16):1752-80 - PubMed
  75. J Mol Endocrinol. 1993 Aug;11(1):37-47 - PubMed
  76. J Chem Inf Model. 2009 Jun;49(6):1514-24 - PubMed
  77. PLoS One. 2011 Apr 15;6(4):e18587 - PubMed
  78. Med Chem. 2011 Jan;7(1):24-31 - PubMed
  79. Adv Drug Deliv Rev. 2002 Mar 31;54(3):355-66 - PubMed
  80. Nat Med. 2004 Apr;10(4):355-61 - PubMed
  81. Biochem Biophys Res Commun. 2003 Aug 15;308(1):148-51 - PubMed
  82. J Med Chem. 2004 Mar 25;47(7):1750-9 - PubMed
  83. Pharmacology. 2005 Jan;73(1):15-22 - PubMed
  84. Yao Xue Xue Bao. 2011 Jan;46(1):19-29 - PubMed
  85. J Mol Model. 2012 Jan;18(1):39-51 - PubMed
  86. Anal Biochem. 2008 Apr 15;375(2):388-90 - PubMed
  87. Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):450-4 - PubMed
  88. Biophys Chem. 1988 May;30(1):3-48 - PubMed

Substances

MeSH terms

Publication Types