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Prediction of a new surface binding pocket and evaluation of inhibitors against huntingtin interacting protein 14: an insight using docking studies

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Abstract

Protein—protein interactions play an important role in regulating the expression of huntingtin protein (htt). Expansion of polyglutamine tracts in htt results in neurodegenerative Huntington disease. Huntingtin interacting protein (HIP14) is an important interacting partner of htt and the altered interactions have been proposed to play an important role in disease progression. In the present study, an attempt has been made to explore the potential of several known Huntington inhibitors to inhibit HIP14. The docking studies have resulted in the identification of a novel binding site for these inhibitors distinct from the previously known ankyrin repeat domain. The results have been validated using geometry based docking transformations against the other binding pocket. The specificity of binding has been determined with high values of both accuracy and precision. Nine potential inhibitors obtained after screening belong to three distinct classes of compounds viz, carbohydrates (deoxy-glucose), alcohols (including phenolic scaffold) and tetracycline. The compounds form stable complex with protein exhibiting optimal intermolecular and Gibbs free energy. The hydrogen bonding and hydrophobic interactions predominantly contribute to the stability of these complexes. The present study identifies metoprolol, minocyclines and 18 F fluorodeoxyglucose as the best inhibitors that bind specifically to the new site. Therefore, these compounds can further be exploited for their potential to serve in the diagnosis and treatment of Huntington disease. The quantitative predictions provide a scope for experimental testing in future.

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Abbreviations

HIP14:

Huntingtin interacting protein

Htt:

Huntingtin protein

References

  1. Huang KYA, Kang R, Arstikaitis P, Singaraja RR, Metzler M et al (2004) Huntingtin interacting protein HIP14, is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins. Neuron 44:977–986

    Article  CAS  Google Scholar 

  2. Yanai A, Huang K, Kang R, Singaraja RR, Arstikaitis P, Gan L et al (2006) Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nat Neurosci 9:824–831

    Article  CAS  Google Scholar 

  3. Singaraja RR, Hadano S, Metzler M, Givan S, Wellington CL, Warby S et al (2002) HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis. Hum Mol Genet 11:2815–2828

    Article  CAS  Google Scholar 

  4. SEM DCE, French KJ, Upson JJ, Smith CD (2004) Huntingtin interacting protein 14 is an oncogenic human protein: palmitoyl 9230–9237acyltransferase. Oncogene 23:9230–9237

    Google Scholar 

  5. Ghose AK, Viswanadhan VN, Wendoloski JJ (1999) A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem 1:55–68

    Article  CAS  Google Scholar 

  6. Gao T, Collins RE, Horton JR, Zhang X, Zhang R, Dhayalan A et al (2009) The ankyrin repeat domain of Huntingtin interacting protein 14 contains a surface aromatic cage, a potential site for methyl-lysine binding. Proteins 76:772–777

    Article  CAS  Google Scholar 

  7. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H et al (2000) The Protein Data Bank. Nucleic Acids Res 28:235–242

    Article  CAS  Google Scholar 

  8. SYBYL-X 1.1, Tripos International. (1699) South Hanley Rd, St Louis, Missouri, 63144, USA

  9. Bikadi Z, Hazai E (2009) Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock. J Cheminformatics 1:15

    Article  Google Scholar 

  10. Labute P (2007) Protonate 3D: Assignment of Macromolecular Protonation State and Geometry. Chemical Computing Group Inc.

  11. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK et al (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662

    Article  CAS  Google Scholar 

  12. Mark HEF, Geoffrey H, Bernhard P, Peter R, Ian HW (2009) The WEKA Data Mining Software: An Update. SIGKDD Explor 11:10–18

    Article  Google Scholar 

  13. Guha R, Howard MT, Hutchison GR, Murray-Rust P, Rzepa H, Steinbeck C et al (2006) The Blue Obelisk-interoperability in chemical informatics. J Chem Inf Model 46:991–998

    Article  CAS  Google Scholar 

  14. Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson HJ (2005) PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res 33:W363–367

    Article  CAS  Google Scholar 

  15. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS et al (2009) AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791

    Article  CAS  Google Scholar 

  16. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC et al (2004) UCSF Chimera–a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612

    Article  CAS  Google Scholar 

  17. Shaikh SA, Ahmed SR, Jayaram B (2004) A molecular thermodynamic view of DNA-drug interactions: a case study of 25 minor-groove binders. Arch Biochem Biophys 429:81–99

    Article  CAS  Google Scholar 

  18. Sikic M, Tomic S, Vlahovicek K (2009) Prediction of protein-protein interaction sites in sequences and 3D structures by random forests. PLoS Comput Biol 5:e1000278

    Article  Google Scholar 

  19. Egan WJ, Lauri G (2003). Prediction of molecular polar surface area and bioabsorption. Pharmacopeia, Inc.

  20. Sarah LK NL, Nancy B, Peter JT, Lei X, Philip EB (2009) Drug Discovery Using Chemical Systems Biology:Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis. PLoS Comput Biol 5

  21. KAKR SVK, Singh RK, Singh PP (2008) Hydrophobic, Polar and Hydrogen Bonding Based Drug-Receptor Interaction of Tetrahydroimidazobenzodiazepinones. Am J Immunol 4:33–42

    Article  Google Scholar 

  22. Thomas M, Ashizawa T, Jankovic J (2004) Minocycline in Huntington's disease: a pilot study. Mov Disord 19:692–695

    Article  Google Scholar 

  23. Sonnhammer Erik LLHV (2005) Scoredist: A simple and robust protein sequence distance estimator. BMC Bioinformatics 6

  24. YF AFR, Linyi C, Nicholas GD (2002) US Patent 6522975- Prediction of molecular polar surface area and bioabsorption. J Cell Biol 159:23–28

    Article  Google Scholar 

  25. Jain AN (2000) Scoring Functions for Protein-Ligand Docking. Curr Protein Pept Sci 7:407–20

    Article  Google Scholar 

  26. Heron DE, Ferris RL, Karamouzis M, Andrade RS, Deeb EL, Burton S et al (2009) Stereotactic body radiotherapy for recurrent squamous cell carcinoma of the head and neck: results of a phase I dose-escalation trial. Int J Radiat Oncol Biol Phys 75:1493–1500

    Article  Google Scholar 

  27. Mazziotta JC, Phelps ME, Pahl JJ, Huang SC, Baxter LR, Riege WH et al (1987) Reduced cerebral glucose metabolism in asymptomatic subjects at risk for Huntington's disease. N Engl J Med 316:357–362

    Article  CAS  Google Scholar 

  28. Lai RC, Xu MX, Huang WQ, Wang XD, Zeng WA, Lin WQ (2006) Beneficial effects of metoprolol on perioperative cardiac function of elderly esophageal cancer patients. Ai Zheng 25:609–613

    Google Scholar 

  29. JMP KK, Andrew JN, McDonald JT, Sun Y, Micewicz E et al (2009) High-Throughput Screening Identifies Two Classes of Antibiotics as Radioprotectors: Tetracyclines and Fluoroquinolones. Clin Cancer Res 15:7238–7245

    Article  Google Scholar 

  30. Fandos R, Fernandez-Gallardo J, Otero A, Rodriguez A, Ruiz MaJ (2010) nfluence of Hydrogen Bonds on the Stability of Some Cationic Monoaminocarbene Tantalum Complexes Containing Tridentate Bis(phenolato) [OSO]-Type Ligands. Organometallics 29:5834–5840

    Article  CAS  Google Scholar 

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Acknowledgments

The support of Department of Biotechnology, Ministry of Science and Technology, Government of India, to Bioinformatics Centre at Biotech Park Lucknow is gratefully acknowledged.

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Authors and Affiliations

  1. Biotech Park, Sector-G Jankipuram, Lucknow, 226021, Uttar Pradesh, India

    Shipra Gupta, Gauri Misra & Prahlad Kishor Seth

  2. Department of Radiotherapy, C. S. M. Medical University, Shahmina Road, Lucknow, 226003, Uttar Pradesh, India

    Mohan C. Pant

Authors
  1. Shipra Gupta
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  2. Gauri Misra
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  3. Mohan C. Pant
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  4. Prahlad Kishor Seth
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Correspondence to Shipra Gupta.

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Gupta, S., Misra, G., Pant, M.C. et al. Prediction of a new surface binding pocket and evaluation of inhibitors against huntingtin interacting protein 14: an insight using docking studies. J Mol Model 17, 3047–3056 (2011). https://doi.org/10.1007/s00894-011-1005-8

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  • DOI: https://doi.org/10.1007/s00894-011-1005-8

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