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Journal of Molecular Modeling

, 23:272 | Cite as

Docking-assisted 3D-QSAR studies on xanthones as α-glucosidase inhibitors

  • Xuehua Zheng
  • Siyuan Zhou
  • Chen Zhang
  • Deyan Wu
  • Hai-Bin Luo
  • Yinuo WuEmail author
Original Paper

Abstract

Recently, a series of xanthone analogues has been identified as α-glucosidase inhibitors. To provide deeper insight into the three-dimensional (3D) structural requirements for the activities of these molecules, CoMFA and CoMSIA approaches were employed on 54 xanthones to construct 3D-QSAR models. Their bioactive conformations were first investigated by docking studies and optimized by subsequent molecular dynamics (MD) simulations using the homology modeled structure of the target protein. Based on the docking/MD-determined conformers, 3D-QSAR studies generated several significant models in terms of 47 molecules as the training set. The best model (CoMSIA-SHA) yielded q 2 of 0.713, r 2 of 0.967 and F of 140.250. The robustness of the model was further externally confirmed by a test set of the remaining molecules (q 2 = 0.793, r 2 = 0.902, and k = 0.905). Contour maps provided much information for future design and optimization of new compounds with high inhibitory activities towards α-glucosidase.

Graphical Abstract

CoMSIA/SHA contour map of xanthone α-glucosidase inhibitor

Keywords

Xanthone derivatives α-glucosidase Docking 3D-QSAR Homology modeling 

Notes

Acknowledgements

This work was supported by the Natural Science Foundation of China (21572279, 81373258, 81522041, and 81602968); the Medical Scientific Research Foundation of Guangdong Province (A2016201); the Natural Science Foundation of Guangdong Province (2014A020210009 and 2016A030313589); Science Foundation of Guangzhou City (2014 J4100165); Science and Technology Program of Guangzhou (201605101030072 and 201707010049); Guangdong Province Higher Vocational Colleges & Schools Pearl River Scholar Funded Scheme (2016); and Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase).

Supplementary material

894_2017_3438_MOESM1_ESM.doc (112 kb)
ESM 1 (DOC 111 kb)

References

  1. 1.
    International Diabetes Federation (2015) IDF Diabetes Atlas, 7th edn. International Diabetes Federation, BrusselsGoogle Scholar
  2. 2.
    Yang L, Shao J, Bian Y, Wu H, Shi L, Zeng L, Li W, Dong J (2016) Prevalence of type 2 diabetes mellitus among inland residents in China (2000-2014): a meta-analysis. J Diabetes Investig 7:845–852CrossRefGoogle Scholar
  3. 3.
    Joshi SR, Standl E, Tong N, Shah P, Kalra S, Rathod R (2015) Therapeutic potential of alpha-glucosidase inhibitors in type 2 diabetes mellitus: an evidence-based review. Expert Opin Pharmacother 16:1959–1981CrossRefGoogle Scholar
  4. 4.
    Derosa G, Maffioli P (2012) Alpha-Glucosidase inhibitors and their use in clinical practice. Arch Med Sci 8:899–906CrossRefGoogle Scholar
  5. 5.
    Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, Rutten GE, Van Weel C (2005) Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev, CD003639Google Scholar
  6. 6.
    Sim L, Jayakanthan K, Mohan S, Nasi R, Johnston BD, Pinto BM, Rose DR (2010) New glucosidase inhibitors from an ayurvedic herbal treatment for type 2 diabetes: structures and inhibition of human intestinal maltase-glucoamylase with compounds from Salacia reticulata. Biochemistry 49:443–451CrossRefGoogle Scholar
  7. 7.
    Riaz S, Khan IU, Yar M, Ashraf M, Rehman TU, Shaukat A, Jamal SB, Duarte VC, Alves MJ (2014) Novel pyridine-2,4,6-tricarbohydrazide derivatives: design, synthesis, characterization and in vitro biological evaluation as alpha- and beta-glucosidase inhibitors. Bioorg Chem 57:148–154CrossRefGoogle Scholar
  8. 8.
    Mukherjee A, Sengupta S (2013) Characterization of nimbidiol as a potent intestinal disaccharidase and glucoamylase inhibitor present in Azadirachta indica (neem) useful for the treatment of diabetes. J Enzyme Inhib Med Chem 28:900–910CrossRefGoogle Scholar
  9. 9.
    Wang Q, Zhang L, Bian X, Wang Y (2014) Progress in research of alpha-glucosidase inhibitor and the structure-activity relationship. Chin J New Drugs 23:189–195Google Scholar
  10. 10.
    Liu Y, Zou L, Ma L, Chen WH, Wang B, Xu ZL (2006) Synthesis and pharmacological activities of xanthone derivatives as alpha-glucosidase inhibitors. Bioorg Med Chem 14:5683–5690CrossRefGoogle Scholar
  11. 11.
    Liu Y, Ma L, Chen WH, Wang B, Xu ZL (2007) Synthesis of xanthone derivatives with extended pi-systems as alpha-glucosidase inhibitors: insight into the probable binding mode. Bioorg Med Chem 15:2810–2814CrossRefGoogle Scholar
  12. 12.
    Liu Y, Ke Z, Cui J, Chen WH, Ma L, Wang B (2008) Synthesis, inhibitory activities, and QSAR study of xanthone derivatives as alpha-glucosidase inhibitors. Bioorg Med Chem 16:7185–7192CrossRefGoogle Scholar
  13. 13.
    Li GL, He JY, Zhang A, Wan Y, Wang B, Chen WH (2011) Toward potent alpha-glucosidase inhibitors based on xanthones: a closer look into the structure-activity correlations. Eur J Med Chem 46:4050–4055CrossRefGoogle Scholar
  14. 14.
    Discovery Studio 2.5.5 (2009) Accelrys, San Diego, CAGoogle Scholar
  15. 15.
    Li Z, Cai YH, Cheng YK, Lu X, Shao YX, Li X, Liu M, Liu P, Luo HB (2013) Identification of novel phosphodiesterase-4D inhibitors prescreened by molecular dynamics-augmented modeling and validated by bioassay. J Chem Inf Model 53:972–981CrossRefGoogle Scholar
  16. 16.
    Li Z, Lu X, Feng LJ, Gu Y, Li X, Wu Y, Luo HB (2015) Molecular dynamics-based discovery of novel phosphodiesterase-9A inhibitors with non-pyrazolopyrimidinone scaffolds. Mol BioSyst 11:115–125CrossRefGoogle Scholar
  17. 17.
    Emsley P, Lohkamp B, Scott WG, Cowtan K (2010) Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66:486–501CrossRefGoogle Scholar
  18. 18.
    MOE 2010 (2010) Chemical Computing Group Inc., Montreal, Quebec, CanadaGoogle Scholar
  19. 19.
    Sybyl 7.3 (2006) Tripos Associates, St. Louis, MOGoogle Scholar
  20. 20.
    The PyMOL Molecular Graphics System (2002) De-Lano Scientific, San Carlos, CAGoogle Scholar
  21. 21.
    Case DA, Babin V, Berryman J, Betz RM, Cai Q, Cerutti DS, et al (2014) Amber 14. University of California, San FranciscoGoogle Scholar
  22. 22.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR et al (2004) Gaussian 03, Gaussian Inc., Wallingford, CTGoogle Scholar
  23. 23.
    Wang J, Wang W, Kollman PA, Case DA (2001) Antechamber: an accessory software package for molecular mechanical calculations. J Am Chem Soc 222:U403Google Scholar
  24. 24.
    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(33-8):27–28Google Scholar
  25. 25.
    Zheng XH, Shao YX, Li Z, Liu M, Bu X, Luo HB, Hu X (2012) Quantitative structure-retention relationship of curcumin and its analogues. J Sep Sci 35:505–512CrossRefGoogle Scholar
  26. 26.
    Lee Y, Kim S, Kim JY, Arooj M, Kim S, Hwang S, Kim BW, Park KH, Lee KW (2014) Binding mode analyses and pharmacophore model development for stilbene derivatives as a novel and competitive class of alpha-glucosidase inhibitors. PLoS One 9:e85827CrossRefGoogle Scholar
  27. 27.
    Bharatham K, Bharatham N, Park KH, Lee KW (2008) Binding mode analyses and pharmacophore model development for sulfonamide chalcone derivatives, a new class of alpha-glucosidase inhibitors. J Mol Graph Model 26:1202–1212CrossRefGoogle Scholar
  28. 28.
    Park H, Hwang KY, Oh KH, Kim YH, Lee JY, Kim K (2008) Discovery of novel alpha-glucosidase inhibitors based on the virtual screening with the homology-modeled protein structure. Bioorg Med Chem 16:284–292CrossRefGoogle Scholar
  29. 29.
    Ferreira SB, Sodero AC, Cardoso MF, Lima ES, Kaiser CR, Silva FP, Ferreira VF (2010) Synthesis, biological activity, and molecular modeling studies of 1H-1,2,3-triazole derivatives of carbohydrates as alpha-glucosidases inhibitors. J Med Chem 53:2364–2375CrossRefGoogle Scholar
  30. 30.
    Yamamoto K, Miyake H, Kusunoki M, Osaki S (2010) Crystal structures of isomaltase from Saccharomyces cerevisiae and in complex with its competitive inhibitor maltose. FEBS J 277:4205–4214CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Xuehua Zheng
    • 1
  • Siyuan Zhou
    • 2
  • Chen Zhang
    • 2
  • Deyan Wu
    • 2
  • Hai-Bin Luo
    • 2
    • 3
  • Yinuo Wu
    • 2
    Email author
  1. 1.School of Pharmaceutical SciencesGuangzhou Medical UniversityGuangzhouChina
  2. 2.School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhouChina
  3. 3.Collaborative Innovation Center of High Performance ComputingNational University of Defense TechnologyChangshaChina

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