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Journal of Molecular Modeling

, 25:272 | Cite as

In silico investigations on the binding efficacy and allosteric mechanism of six different natural product compounds towards PTP1B inhibition through docking and molecular dynamics simulations

  • Baskaran SarathKumar
  • Baddireddi Subhadra LakshmiEmail author
Original Paper
  • 83 Downloads

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both the insulin and leptin receptor phosphorylation which impacts insulin sensitivity and hence is a major therapeutic target for the treatment of type 2 diabetes and obesity. Identification of PTP1B active site inhibitors has proven to be difficult with none of them clearing the phase II clinical trials. Since the conventional methods of targeting the active site of PTP1B have failed to bring out effective PTP1B inhibitors as potential drugs, recent studies are focussing on identification of potential allosteric inhibitors of PTP1B with better specificity and activity. A complete understanding of the molecular features dynamically involved for allosteric site inhibition is still uncertain, and hence, this study is aimed at evaluating the allosteric effectiveness of six natural compounds isolated from medicinal plants which showed in vitro antidiabetic activity along with PTP1B inhibition. The allosteric binding and inhibition of these compounds are studied using computational methods such as molecular docking, homology modelling and molecular dynamics simulations for a timescale of 100 ns. The molecular dynamics simulations of native PTP1B, along with the modelled allosteric α-7 helix, for a timescale of 100 ns, revealed the spontaneous transition of the native PTP1B from open WPD loop (active) to closed WPD loop (inactive) conformations during the simulations. Similar dynamics was observed in the presence of the active site substrate pTyr (phosphotyrosine), whereas this transition was inhibited in the presence of the compounds at the allosteric site. Results of molecular dynamics simulations and principal component analysis reveal that the hindrance to WPD loop was mediated through structural interactions between the allosteric α-helical triad with Loop11 and WPD loop. The MM-PBSA (Molecular Mechanics - Poisson Boltzmann with Surface Area solvation) binding energy results along with H-bonding analysis show the possible allosteric inhibition of Aloe emodin glycoside (AEG), 3β-taraxerol (3BT), chlorogenic acid (CGA) and cichoric acid (CHA) to be higher in comparison with (3β)-stigmast-5-en-3-ol (SGS) and methyl lignocerate (MLG). The interaction analysis was further validated by scoring the allosteric complexes before and after MD simulations using Glide. These findings on spontaneous PTP1B fluctuations and the allosteric interactions provide a better insight into the role of PTP1B fluctuations in impacting the binding energy of allosteric inhibitors towards optimal drug designing for PTP1B.

Graphical abstract

Keywords

Molecular docking Homology modelling Molecular dynamics simulation PTP1B allosteric inhibitors PCA MM-PBSA analysis Glide docking Binding energy analysis Allosteric α-7 helix 

Notes

Acknowledgements

The authors thank Dr. T. Kothai and Dr. P. Gautam for their constant support and encouragement. The authors are grateful to Dr. Subrata Chattopadhyay (C-DAC) and Janaki Chintalapati (C-DAC) for providing access to computational resources of the GARUDA Cluster facility, C-DAC, Government of India, to run the Gromacs v4.0.5-MD Simulations during 2013–2015.

Funding information

The authors thank the Department of Biotechnology, Govt of India for financial assistance for the HPC cluster computer for Drug Design and related commercial Schrodinger software through the DBT-BUILDER (BT/PR12153/INF/22/200/2014)., and the DBT-BTIS-DIC facility at Centre for Biotechnology, Anna University, Chennai. The author Mr. SarathKumar B sincerely thanks the Council for Scientific and Industrial Research, Govt. of India, for financial assistance as CSIR-SRF (09/468(0480)/2014-EMR-1).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

894_2019_4172_MOESM1_ESM.docx (28.3 mb)
ESM 1 (DOCX 28.2 mb)

References

  1. 1.
    Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283(5407):1544–1548CrossRefGoogle Scholar
  2. 2.
    Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, Stricker-Krongrad A, Shulman GI, Neel BG, Kahn BB (2000) Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 20(15):5479–5489CrossRefGoogle Scholar
  3. 3.
    Fauman EB, Saper MA (1996) Structure and function of the protein tyrosine phosphatases. Trends Biochem Sci 21(11):413–417CrossRefGoogle Scholar
  4. 4.
    Barford D, Flint AJ, Tonks NK (1994) Crystal structure of human protein tyrosine phosphatase 1B. Science 263(5152):1397–1404CrossRefGoogle Scholar
  5. 5.
    Zhang ZY (2001) Protein tyrosine phosphatases: prospects for therapeutics. Curr Opin Chem Biol 5(4):416–423CrossRefGoogle Scholar
  6. 6.
    Johnson TO, Ermolieff J, Jirousek MR (2002) Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discov 1(9):696–709CrossRefGoogle Scholar
  7. 7.
    Kolmodin K, Aqvist J (2001) The catalytic mechanism of protein tyrosine phosphatases revisited. FEBS Lett 498(2–3):208–213CrossRefGoogle Scholar
  8. 8.
    Montalibet J, Skorey K, McKay D, Scapin G, Asante-Appiah E, Kennedy BP (2006) Residues distant from the active site influence protein-tyrosine phosphatase 1B inhibitor binding. J Biol Chem 281(8):5258–5266CrossRefGoogle Scholar
  9. 9.
    Jia Z, Barford D, Flint AJ, Tonks NK (1995) Structural basis for Phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B. Science 268(5218):1754–1758CrossRefGoogle Scholar
  10. 10.
    Kamerlin SC, Rucker R, Boresch S (2007) Molecular dynamics study of WPD-loop flexibility in PTP1B. Biochem Biophys Res Commun 356(4):1011–1016CrossRefGoogle Scholar
  11. 11.
    Wiesmann C, Barr KJ, Kung J, Zhu J, Erlanson DA, Shen W, Fahr BJ, Zhong M, Taylor L, Randal M, McDowell RS, Hansen SK (2004) Allosteric inhibition of protein tyrosine phosphatase-1B. Nat Struct Mol Biol 11(8):730–737CrossRefGoogle Scholar
  12. 12.
    Olmez EO, Alakent B (2011) Alpha7 helix plays an important role in the conformational stability of PTP1B. J Biomol Struct Dyn 28(5):675–693CrossRefGoogle Scholar
  13. 13.
    Bharatham K, Bharatham N, Kwon YJ, Lee KW (2008) Molecular dynamics simulation study of PTP1B with allosteric inhibitor and its application in receptor based pharmacophore modeling. J Comput Aided Mol Des 22(12):925–933CrossRefGoogle Scholar
  14. 14.
    Muthusamy VS, Anand S, Sangeetha KN, Sujatha S, Arun B, Lakshmi BS (2008) Tannins present in Cichorium intybus enhance glucose uptake and inhibit adipogenesis in 3T3-L1 adipocytes through PTP1B inhibition. Chem Biol Interact 174:69–78CrossRefGoogle Scholar
  15. 15.
    Muthusamy VS, Saravanababu C, Ramanathan M, Bharathi Raja R, Sudhagar S, Anand S, Lakshmi BS (2010) Inhibition of protein tyrosine phosphatase 1B and regulation of insulin signalling markers by caffeoyl derivatives of chicory (Cichorium intybus) salad leaves. Br J Nutr 104(6):813–823CrossRefGoogle Scholar
  16. 16.
    Anand S, Muthusamy VS, Sujatha S, Sangeetha KN, Bharathi Raja R, Sudhagar S, Poornima Devi N, Lakshmi BS (2010) Aloe emodin glycosides stimulates glucose transport and glycogen storage through PI3K dependent mechanism in L6 myotubes and inhibits adipocyte differentiation in 3T3L1 adipocytes. FEBS Lett 584(14):3170–3178CrossRefGoogle Scholar
  17. 17.
    Sangeetha KN, Sujatha S, Muthusamy VS, Anand S, Nithya N, Velmurugan D, Balakrishnan A, Lakshmi BS (2010) 3beta-taraxerol of Mangifera indica, a PI3K dependent dual activator of glucose transport and glycogen synthesis in 3T3-L1 adipocytes. Biochim Biophys Acta 1800(3):359–366CrossRefGoogle Scholar
  18. 18.
    Sujatha S, Anand S, Sangeetha KN, Shilpa K, Lakshmi J, Balakrishnan A, Lakshmi BS (2010) Biological evaluation of (3β)-STIGMAST-5-EN-3-OL as potent anti-diabetic agent in regulating glucose transport using in vitro model. Int J Diabetes Mellitus 2(2):101–109CrossRefGoogle Scholar
  19. 19.
    Shilpa K, Sangeetha KN, Muthusamy VS, Sujatha S, Lakshmi BS (2009) Probing key targets in insulin signaling and adipogenesis using a methanolic extract of Costus pictus and its bioactive molecule, methyl tetracosanoate. Biotechnol Lett 31(12):1837–1841CrossRefGoogle Scholar
  20. 20.
    Popov D (2011) Novel protein tyrosine phosphatase 1B inhibitors: interaction requirements for improved intracellular efficacy in type 2 diabetes mellitus and obesity control. Biochem Biophys Res Commun 410(3):377–381CrossRefGoogle Scholar
  21. 21.
    Panzhinskiy E, Ren J, Nair S (2013) Pharmacological inhibition of protein tyrosine phosphatase 1B: a promising strategy for the treatment of obesity and type 2 diabetes mellitus. Curr Med Chem 20(21):2609–2625CrossRefGoogle Scholar
  22. 22.
    Sarath Kumar B, Goswami N, Selvaraj S, Muthusamy VS, Lakshmi BS (2012) Molecular dynamics approach to probe the allosteric inhibition of PTP1B by chlorogenic and cichoric acid. J Chem Inf Model 52(8):2004–2012CrossRefGoogle Scholar
  23. 23.
    Krishnan N, Koveal D, Miller DH, Xue B, Akshinthala SD, Kragelj J, Jensen MR, Gauss CM, Page R, Blackledge M, Muthuswamy SK, Peti W, Tonks NK (2014) Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nat Chem Biol 10(7):558–566CrossRefGoogle Scholar
  24. 24.
    Jin T, Yu H, Huang XF (2016) Selective binding modes and allosteric inhibitory effects of lupane triterpenes on protein tyrosine phosphatase 1B. Sci Rep 6:20766-1–20766-14Google Scholar
  25. 25.
    Zargari F, Lotfi M, Shahraki O, Nikfarjam Z, Shahraki J (2018) Flavonoids as potent allosteric inhibitors of protein tyrosine phosphatase 1B: molecular dynamics simulation and free energy calculation. J Biomol Struct Dyn 36(15):4126–4142CrossRefGoogle Scholar
  26. 26.
    Shinde RN, Kumar GS, Eqbal S, Sobhia ME (2018) Screening and identification of potential PTP1B allosteric inhibitors using in silico and in vitro approaches. PLoS One 13(6):e0199020CrossRefGoogle Scholar
  27. 27.
    Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) Autodock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 16:2785–2791CrossRefGoogle Scholar
  28. 28.
    Puius YA, Zhao Y, Sullivan M, Lawrence DS, Almo SC, Zhang ZY (1997) Identification of a second aryl phosphate-binding site in protein-tyrosine phosphatase 1B: a paradigm for inhibitor design. Proc Natl Acad Sci U S A 94(25):13420–13425CrossRefGoogle Scholar
  29. 29.
    Pedersen AK, Gü PG, Møller KB, Iversen LF, Kastrup JS (2004) Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B. Acta Crystallogr D Biol Crystallogr 60(Pt 9):1527–1534CrossRefGoogle Scholar
  30. 30.
    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 25(13):1605–1612CrossRefGoogle Scholar
  31. 31.
    Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and and empirical binding free energy function. J Comput Chem 19(14):1639–1662CrossRefGoogle Scholar
  32. 32.
    Webb B, Sali A (2016) Comparative protein structure modeling using MODELLER. Curr Protoc Bioinformatics 54:5.6.1–5.6.37Google Scholar
  33. 33.
    Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible and free. J Comput Chem 26(16):1701–1718CrossRefGoogle Scholar
  34. 34.
    Hess B, Kutzner C, Van Der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4(3):435–447CrossRefGoogle Scholar
  35. 35.
    Schüttelkopf AW, Van Aalten DM (2004) PRODRG - a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 60(Pt 8):1355–1363CrossRefGoogle Scholar
  36. 36.
    Turner PJ. XMGRACE, version 5. Center for Coastal and Land-Margin Research, Oregon Graduate Institute of Science and Technology, Beaverton, Oregon; 2005. http://plasma-gate.weizmann.ac.il/Grace/
  37. 37.
    Kumari R, Kumar R, Lynn A (2014) g_mmpbsa-a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 54(7):1951–1962CrossRefGoogle Scholar
  38. 38.
    Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47:1750–1759CrossRefGoogle Scholar
  39. 39.
    Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 49(21):6177–6196CrossRefGoogle Scholar
  40. 40.
    Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27(3):221–234CrossRefGoogle Scholar
  41. 41.
    Shinde RN, Sobhia ME (2013) Binding and discerning interactions of PTP1B allosteric inhibitors: novel insights from molecular dynamics simulations. J Mol Graph Model 45:98–110CrossRefGoogle Scholar
  42. 42.
    Kumar R, Shinde RN, Ajay D, Sobhia ME (2010) Probing interaction requirements in PTP1B inhibitors: a comparative molecular dynamics study. J Chem Inf Model 50(6):1147–1158CrossRefGoogle Scholar
  43. 43.
    Peters GH, Frimurer TM, Andersen JN, Olsen OH (1999) Molecular dynamics simulations of protein-tyrosine phosphatase 1B. I ligand-induced changes in protein motions. Biophys J 77(1):505–515CrossRefGoogle Scholar
  44. 44.
    Peters GH, Frimurer TM, Andersen JN, Olsen OH (2000) Molecular dynamics simulations of protein-tyrosine phosphatase 1B. II Substrate-enzyme interactions and dynamics. Biophys J 78(5):2191–2200CrossRefGoogle Scholar
  45. 45.
    Kamerlin SC, Rucker R, Boresch S (2006) A targeted molecular dynamics study of WPD loop movement in PTP1B. Biochem Biophys Res Commun 345(3):1161–1166CrossRefGoogle Scholar
  46. 46.
    Cui W, Geng LL, Liang DS, Hou TJ, Ji MJ (2013) Unraveling the allosteric inhibition mechanism of PTP1B by free energy calculation based on umbrella sampling. J Chem Inf Model 53(5):1157–1167CrossRefGoogle Scholar
  47. 47.
    Li S, Zhang J, Lu S, Huang W, Geng L, Shen Q, Zhang J (2014) The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B. PLoS One 9(5):e97668CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Baskaran SarathKumar
    • 1
  • Baddireddi Subhadra Lakshmi
    • 1
    Email author
  1. 1.Department of BiotechnologyAnna UniversityChennaiIndia

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