Molecular Pharmacology

Molecular dynamics simulations of interaction between protein-tyrosine phosphatase 1B and a bidentate inhibitor

Abstract

Aim:

To investigate the dynamic properties of protein-tyrosine phosphatase (PTP) 1B and reveal the structural factors responsible for the high inhibitory potency and selectivity of the inhibitor SNA for PTP1B.

Methods:

We performed molecular dynamics (MD) simulations using a long time-scale for both PTP1B and PTP1B complexed with the inhibitor SNA, the most potent and selective PTP1B inhibitor reported to date. The trajectories were analyzed by using principal component analysis.

Results:

Trajectory analyses showed that upon binding the ligand, the flexibility of the entire PTP1B molecule decreases. The most notable change is the movement of the WPD-loop. Our simulation results also indicated that electrostatic interactions contribute more to PTP1B-SNA complex conformation than the van der Waals interactions, and that Lys41, Arg47, and Asp48 play important roles in determining the conformation of the inhibitor SNA and in the potency and selectivity of the inhibitor. Of these, Arg47 contributed most. These results were in agreement with previous experimental results.

Conclusion:

The information presented here suggests that potent and selective PTP1B inhibitors can be designed by targeting the surface residues, for example the region containing Lys41, Arg47, and Asp48, instead of the second phosphate binding site (besides the active phosphate binding site).

References

  1. 1

    Ripka WC . In: Doherty AM editor . Annual Reports in medicinal chemistry, volume 35. San Diego, CA: Academic Press; 2000. p 231–50.

    Google Scholar 

  2. 2

    Johnson TO, Ermolieff J, Jirousek M . Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discovery 2002; 1: 696–709.

    CAS  Article  Google Scholar 

  3. 3

    Blaskovich MA, Kim HO . Recent discovery and development of protein tyrosine phosphatase inhibitors. Expert Opin Ther Pat 2002; 12: 871–905.

    CAS  Article  Google Scholar 

  4. 4

    Shen K, Keng YF, Wu L, Guo XL, Lawrence DS, Zhang ZY . Acquisition of a specific and potent PTP 1B inhibitor from a novel combinatorial library and screening procedure. J Biol Chem 2001; 276: 47311–9.

    CAS  Article  Google Scholar 

  5. 5

    Xie J, Seto CT . Investigations of linker structure on the potency of a series of bidentate protein tyrosine phosphatase inhibitors. Bioorg Med Chem 2005; 13: 2981–91.

    CAS  Article  Google Scholar 

  6. 6

    Dixit M, Tripathi BK, Srivastava AK, Goel A . Synthesis of functionalized acetophenones as protein tyrosine phosphatase 1B inhibitors. Bioorg Med Chem Lett 2005; 15: 3394–7.

    CAS  Article  Google Scholar 

  7. 7

    Shim YS, Kim KC, Lee KA, Shrestha S, Lee KH, Kim CK, et al. Formylchromone derivatives as irreversible and selective inhibitors of human protein tyrosine phosphatase 1B. Kinetic and modeling studies. Bioorg Med Chem 2005; 13: 1325–32.

    CAS  Article  Google Scholar 

  8. 8

    Ockey DA, Gadek TR . Discovery of novel PTP1b inhibitors. Bioorg Med Chem Lett 2004; 14: 389–91.

    CAS  Article  Google Scholar 

  9. 9

    Zhao HY, Liu G, Xin ZL, Serby MD, Pei ZH, Szczepankiewicz BG, et al. Isoxazole carboxylic acids as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Bioorg Med Chem Lett 2004; 14: 5543–6.

    CAS  Article  Google Scholar 

  10. 10

    Patankar SJ, Jurs PC . Classification of inhibitors of protein tyrosine phosphatase 1B using molecular structure based descriptors. J Chem Inf Comput Sci 2003; 43: 885–99.

    CAS  Article  Google Scholar 

  11. 11

    Zhang ZY, Lee SY . PTP1B inhibitors as potential therapeutics in the treatment of type 2 diabetes and obesity. Expert Opin Investig Drugs 2003; 12: 223–33.

    CAS  Article  Google Scholar 

  12. 12

    Puius YA, Zhao Y, Sullivan M, Lawrence DS, Almo SC, Zhang ZY . Identification of a second aryl phosphate-binding site in protein-tyrosine phosphatase 1B: a paradigm for inhibitor design. Proc Natl Acad Sci USA 1997; 94: 13420–5.

    CAS  Article  Google Scholar 

  13. 13

    Iversen LF, Andersen HS, Moller KB, Olsen OH, Peters GH, Branner S, et al. Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases. Biochemistry 2001; 40: 14812–20.

    CAS  Article  Google Scholar 

  14. 14

    Liu G, Trevillyan JM . Protein tyrosine phosphatase 1B as a target for the treatment of impaired glucose tolerance and type II diabetes. Curr Opin Investig Drugs 2002; 3: 1608–16.

    CAS  PubMed  Google Scholar 

  15. 15

    Taing M, Keng YF, Shen K, Wu L, Laqrence DS, Zhang ZY . Potent and highly selective inhibitors of the protein tyrosine phosphatase 1B. Biochemistry 1999; 276: 3793–803.

    Article  Google Scholar 

  16. 16

    Taylor SD, Kotoris CC, Dinaut AN, Wang Q, Ramachandran C, Huang Z . Potent non-peptidyl inhibitors of protein tyrosine phosphatase 1B. Bioorg Med Chem 1998; 6: 1457–68.

    CAS  Article  Google Scholar 

  17. 17

    Desmarais S, Friesen RW, Zamboni R, Ramachandrn C . [Difluro (phosphono)methyl]phenylalanine-containing peptide inhibitors of protein tyrosine phosphatases. Biochem J 1999; 337: 219–23.

    CAS  Article  Google Scholar 

  18. 18

    Jia Z, Ye Q, Dinaut AN, Wang Q, Waddleton D, Payette P, et al. Structure of protein tyrosine phosphatase 1B in complex with inhibitors bearing two phosphotyrosine mimetics. J Med Chem 2001; 44: 4584–94.

    CAS  Article  Google Scholar 

  19. 19

    Sun JP, Fedorov AA, Lee Y, Guo XL, Shen K, Lawrence DS, et al. Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor. J Biol Chem 2003; 278: 12406–14.

    CAS  Article  Google Scholar 

  20. 20

    Barford D, Flint AJ, Tonks NK . Crystal structure of human protein tyrosine phosphatase 1B. Science 1994; 263: 1397–404.

    CAS  Article  Google Scholar 

  21. 21

    Bernstein FC, Koetzle TF, Williams GJB, Meyer EF, Brice MD, Roger JR, et al. The Protein Data Bank: a computer based archival file for macromolecular structure. J Mol Biol 1977; 112: 535–42.

    CAS  Article  Google Scholar 

  22. 22

    Sybyl [molecular modeling package], version 6.8. St Louis, MO: Tripos Associates; 2000.

  23. 23

    Berendsen HJC, van der Spoel D, van Drunen R . GROMACS: a message-passing parallel molecular dynamics implementation. Comp Phys Commun 1995; 91: 43–56.

    CAS  Article  Google Scholar 

  24. 24

    van der Spoel D, van Buuren AR, Apol E, Meulenhoff PJ, Tieleman DP, Sijbers AL, et al. Gromacs User Manual, Version 3.1. Nijenborgh, The Netherlands: Groningen University; 2002.

    Google Scholar 

  25. 25

    van der Spoel D, van Buuren AR, Tieleman DP, Berendsen HJ . Molecular dynamics simulations of peptides from BPTI: a closer look at amide-aromatic interactions. J Biomol NMR 1996; 8: 229–38.

    CAS  Article  Google Scholar 

  26. 26

    van Gunsteren WF, Berendsen HJ . Gromos-87 manual. Nijenborgh, The Netherlands: Biomos BV; 1987.

    Google Scholar 

  27. 27

    van Aalten DMF, Bywater R, Findlay JBC, Hendlich M, Hooft RWW, Vriend G . PRODRG, a program for generating molecular topologies and unique molecular descriptors from coordinates of small molecules. JCAMD 1996; 10: 255–62.

    CAS  Google Scholar 

  28. 28

    Breneman CM, Wiberg KB . Determining atom-centered mono-poles from molecular electrostatic potentials. The need for high sampling density in formamide conformational analysis. J Comp Chem 1990; 11: 361–97.

    CAS  Article  Google Scholar 

  29. 29

    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian 98, revision A.3. Pittsburgh, PA: Gaussian Inc; 1998.

    Google Scholar 

  30. 30

    Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J . Interaction models for water in relation to protein hydration. In: Pullman B editor Intermolecular forces. Dordrecht, The Netherlands: D Reidel Publishing Company; 1981. p 331–342.

    Google Scholar 

  31. 31

    Berendsen HJC, Postma JPM, DiNola A, Haak JR . Molecular dynamics with coupling to an external bath. J Chem Phys 1984; 81: 3684–90.

    CAS  Article  Google Scholar 

  32. 32

    Hess B, Bekker H, Berendsen HJC, Fraaije JGEM . LINCS: a linear constraint solver for molecular simulations. J Comp Chem 1997; 18: 1463–72.

    CAS  Article  Google Scholar 

  33. 33

    Darden T, York D, Pedersen L . Particle mesh Ewald: an N-log (N) method for Ewald sums in large systems. J Chem Phys 1993; 98: 10089–92.

    CAS  Article  Google Scholar 

  34. 34

    Peters GH, Frimurer TM, Andersen JN, Olsen OH . Molecular dynamics simulations of protein-tyrosine phosphatase 1B. I. ligand-induced changes in the protein motions. Biophys J 1999; 77: 505–15.

    CAS  Article  Google Scholar 

  35. 35

    Lohse DL, Denu JM, Santoro M, Dixon JE . Roles of aspartic acid-181 and serine-222 in intermediate formation and hydrolysis of the mammalian protein-tyrosine-phosphatase PTP1. Biochemistry 1997; 36: 4568–75.

    CAS  Article  Google Scholar 

  36. 36

    Wade RC, Davis ME, Luty BA, Madura JD, McCammon JA . Gating of the active site of triose phosphate isomerase: Brownian dynamics simulations of flexible peptide loops in the enzyme. Biophys J 1993; 64: 9–15.

    CAS  Article  Google Scholar 

  37. 37

    Wade RC, Luty BA, Demchuk E, Madura JD, Davis ME, Briggs JM, et al. Simulation of enzyme-substrate encounter with gated active sites. Nature Struct Biol 1994; 1: 63–67.

    Google Scholar 

  38. 38

    Kempner ES . Movable lobes and flexible loops in proteins. FEBS Lett 1993; 326: 4–10.

    CAS  Article  Google Scholar 

  39. 39

    Philippopoulos M, Xiang Y, Lim C . Identifying the mechanism of protein loop closure: a molecular dynamics simulation of the Bacillus stearothermophilus LDH loop in solution. Protein Eng 1995; 8: 565–73.

    CAS  Article  Google Scholar 

  40. 40

    Falzone CJ, Wright PE, Benkovic SJ . Dynamics of a flexible loop in dihydrofolate reductase from Escherichia coli and its implication for catalysis. Biochemistry 1994; 33: 439–42.

    CAS  Article  Google Scholar 

  41. 41

    Williams JC, MacDermott AE . Dynamics of the flexible loop of triosephosphate isomerase: the loop motion is not ligand gated. Biochemistry 1995; 34: 8309–19.

    CAS  Article  Google Scholar 

  42. 42

    Peters GH, Frimurer TM, Andersen JN, Olsen OH . Molecular dynamics simulations of protein-tyrosine phosphatase 1B. II. Substrate-enzyme interactions and dynamics. Biophys J 2000; 78: 2191–200.

    CAS  Article  Google Scholar 

  43. 43

    Wallace AC, Laskowski RA, Thornton JM . LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng 1995; 8: 127–34.

    CAS  Article  Google Scholar 

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Correspondence to Gui-xia Liu or Hua-liang Jiang.

Additional information

Project supported by the State Key Program of Basic Research of China (No 2002CB-512802), the National Natural Science Foundation of China (No 20372069, 29725203, and 20072042), a Shanghai Science and Technology Commission Grant No 02DJ14006), the Key Project for New Drug Research from the Chinese Academy of Sciences, and the National High Technology Research and Development Program of China (No 2002AA233061, 2002AA104270, 2002AA233011, and 2003AA235030). This work was also supported by the Foundation of East China University of Science and Technology for Research (No YC0142101).

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Liu, Gx., Tan, Jz., Niu, Cy. et al. Molecular dynamics simulations of interaction between protein-tyrosine phosphatase 1B and a bidentate inhibitor . Acta Pharmacol Sin 27, 100–110 (2006). https://doi.org/10.1111/j.1745-7254.2006.00251.x

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Keywords

  • molecular dynamics simulation
  • principal component analysis
  • protein-tyrosine phosphatase 1B
  • type 2 diabetes

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