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Druggable exosites of the human kino-pocketome

  • George Nicola
  • Irina Kufareva
  • Andrey V. Ilatovskiy
  • Ruben AbagyanEmail author
Article

Abstract

Small molecules binding at any of the multiple regulatory sites on the molecular surface of a protein kinase may stabilize or disrupt the corresponding interaction, leading to consequent modulation of the kinase cellular activity. As such, each of these sites represents a potential drug target. Even targeting sites outside the immediate ATP site, the so-called exosites, may cause desirable biological effects through an allosteric mechanism. Targeting exosites can alleviate adverse effects and toxicity that is common when ATP-site compounds bind promiscuously to many other types of kinases. In this study we have identified, catalogued, and annotated all potentially druggable exosites on the protein kinase domains within the existing structural human kinome. We then priority-ranked these exosites by those most amenable to drug design. In order to identify pockets that are either consistent across the kinome, or unique and specific to a particular structure, we have also implemented a normalized representation of all pockets, and displayed these graphically. Finally, we have built a database and designed a web-based interface for users interested in accessing the 3-dimensional representations of these pockets. We envision this information will assist drug discovery efforts searching for untargeted binding pockets in the human kinome.

Keywords

Kinase Kinome Pocket Pocketome Exosite Exositome Drugable Druggable Bioinformatics Cheminformatics Drug discovery Protein Target 

Notes

Acknowledgements

This work was funded by NIH 7-R01-GM074832-05 to RA and American Cancer Society Fellowship PF-07-148-01-CDD to GN.

Supplementary material

10822_2019_276_MOESM1_ESM.xlsx (4.7 mb)
Supplementary file1 (XLSX 4841 kb)

References

  1. 1.
    Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) Science 298(5600):1912PubMedCrossRefGoogle Scholar
  2. 2.
    Technology CS. Kinase-Disease Associations https://www.cellsignal.com/common/content/content.jsp?id=science-tables-kinase-disease. Accessed 2019
  3. 3.
    Cohen P (2002) Nat Rev Drug Discov 1(4):309PubMedCrossRefGoogle Scholar
  4. 4.
    Pytel D, Sliwinski T, Poplawski T, Ferriola D, Majsterek I (2009) Anticancer Agents Med Chem 9(1):66PubMedCrossRefGoogle Scholar
  5. 5.
    Rask-Andersen M, Zhang J, Fabbro D, Schioth HB (2014) Trends Pharmacol Sci 35(11):604PubMedCrossRefGoogle Scholar
  6. 6.
    Bolanos-Garcia VM, Fernandez-Recio J, Allende JE, Blundell TL (2006) Trends Biochem Sci 31(12):654PubMedCrossRefGoogle Scholar
  7. 7.
    Poletto G, Vilardell J, Marin O, Pagano MA, Cozza G, Sarno S, Falques A, Itarte E, Pinna LA, Meggio F (2008) Biochemistry 47(32):8317PubMedCrossRefGoogle Scholar
  8. 8.
    Buchou T, Cochet C (2003) Med Sci (Paris) 19(6–7):709CrossRefGoogle Scholar
  9. 9.
    Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Science 289(5486):1938PubMedCrossRefGoogle Scholar
  10. 10.
    Liu Y, Gray NS (2006) Nat Chem Biol 2(7):358PubMedCrossRefGoogle Scholar
  11. 11.
    Tecle H, Shao J, Li Y, Kothe M, Kazmirski S, Penzotti J, Ding Y-H, Ohren J, Moshinsky D, Coli R, Jhawar N, Bora E, Jacques-O'Hagan S, Wu J (2009) Bioorg Med Chem Lett 19(1):226PubMedCrossRefGoogle Scholar
  12. 12.
    Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, Yan C, McConnell P, Spessard C, Banotai C, Mueller WT, Delaney A, Omer C, Sebolt-Leopold J, Dudley DT, Leung IK, Flamme C, Warmus J, Kaufman M, Barrett S, Tecle H, Hasemann CA (2004) Nat Struct Mol Biol 11(12):1192PubMedCrossRefGoogle Scholar
  13. 13.
    Bogoyevitch MA, Fairlie DP (2007) Drug Discov Today 12(15–16):622PubMedCrossRefGoogle Scholar
  14. 14.
    Müller G, Sennhenn PC, Woodcock T, Neumann L (2010) IDrugs 13(7):457PubMedGoogle Scholar
  15. 15.
    Adrian FJ, Ding Q, Sim T, Velentza A, Sloan C, Liu Y, Zhang G, Hur W, Ding S, Manley P, Mestan J, Fabbro D, Gray NS (2006) Nat Chem Biol 2(2):95PubMedCrossRefGoogle Scholar
  16. 16.
    Davidson W, Frego L, Peet GW, Kroe RR, Labadia ME, Lukas SM, Snow RJ, Jakes S, Grygon CA, Pargellis C, Werneburg BG (2004) Biochemistry 43(37):11658PubMedCrossRefGoogle Scholar
  17. 17.
    Hancock CN, Macias A, Lee EK, Yu SY, MacKerell AD, Shapiro P (2005) J Med Chem 48(14):4586PubMedCrossRefGoogle Scholar
  18. 18.
    Stebbins JL, De SK, Machleidt T, Becattini B, Vazquez J, Kuntzen C, Chen L-H, Cellitti JF, Riel-Mehan M, Emdadi A, Solinas G, Karin M, Pellecchia M (2008) Proc Natl Acad Sci USA 105(43):16809PubMedCrossRefGoogle Scholar
  19. 19.
    Burke JR, Pattoli MA, Gregor KR, Brassil PJ, MacMaster JF, McIntyre KW, Yang X, Iotzova VS, Clarke W, Strnad J, Qiu Y, Zusi FC (2003) J Biol Chem 278(3):1450PubMedCrossRefGoogle Scholar
  20. 20.
    Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, Huber HE, Duggan ME (2005) Bioorg Med Chem Lett 15(3):761PubMedCrossRefGoogle Scholar
  21. 21.
    Nicola G, Vakser IA (2007) Bioinformatics 23(7):789PubMedCrossRefGoogle Scholar
  22. 22.
    Totrov M, Abagyan R (1997) Proteins Suppl 1:215CrossRefGoogle Scholar
  23. 23.
    Chen H, Lyne PD, Giordanetto F, Lovell T, Li J (2006) J Chem Inf Model 46(1):401PubMedCrossRefGoogle Scholar
  24. 24.
    Lovell T, Chen H, Lyne PD, Giordanetto F, Li J (2008) J Chem Inf Model 48(1):246CrossRefGoogle Scholar
  25. 25.
    Moitessier N, Englebienne P, Lee D, Lawandi J, Corbeil CR (2008) Br J Pharmacol 153(Suppl 1):S7PubMedGoogle Scholar
  26. 26.
    Schapira M, Totrov M, Abagyan R (1999) J Mol Recognit 12(3):177PubMedCrossRefGoogle Scholar
  27. 27.
    An J, Totrov M, Abagyan R (2005) Mol Cell Proteomics 4(6):752PubMedCrossRefGoogle Scholar
  28. 28.
    Abagyan R, Kufareva I (2009) The flexible pocketome engine for structural chemical genomics Chemogenomics: concepts and applications of a new design and screening paradigm. Wiley, HobokenGoogle Scholar
  29. 29.
    Sudarsanam S (1999) Kinase.com. La Jolla https://kinase.com/. Accessed 2010
  30. 30.
    Niedner RH, Buzko OV, Haste NM, Taylor A, Gribskov M, Taylor SS (2006) Proteins 63(1):78PubMedCrossRefGoogle Scholar
  31. 31.
    Sharma R, Schürer S, Muskal S (2016) F1000Research 5:1–13CrossRefGoogle Scholar
  32. 32.
    Volkamer A, Eid S, Turk S, Rippmann F, Fulle S (2016) J Chem Inf Model 56(2):335PubMedCrossRefGoogle Scholar
  33. 33.
    Kooistra AJ, Kanev GK, van Linden OPJ, Leurs R, de Esch IJP, de Graaf C (2016) Nucleic Acids Res 44(D1):D365PubMedCrossRefGoogle Scholar
  34. 34.
    Bairoch A, Apweiler R, Wu CH, Barker WC, Boeckmann B, Ferro S, Gasteiger E, Huang H, Lopez R, Magrane M, Martin MJ, Natale DA, ODonovan C, Redaschi N, Yeh LS (2005) Nucleic Acids Res 33:154.Google Scholar
  35. 35.
    SWISS-Prot https://ca.expasy.org/sprot/. Accessed 2019
  36. 36.
    Bottegoni G, Kufareva I, Totrov M, Abagyan R (2009) J Med Chem 52(2):D397CrossRefGoogle Scholar
  37. 37.
    Sheridan RP, Maiorov VN, Holloway MK, Cornell WD, Gao YD (2010) J Chem Inf Model 50(11):2029PubMedCrossRefGoogle Scholar
  38. 38.
    Kufareva I, Ilatovskiy AV, Abagyan R (2012) Nucleic Acids Res 40:D535PubMedCrossRefGoogle Scholar
  39. 39.
    Nicola G, Smith CA, Abagyan R (2008) J Comput Biol 15(3):231PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Knighton DR, Zheng J, Eyck LFT, Ashford VA, Xuong N-H, Taylor SS, Sowadski JM, Eyck LFTEN (1991) Adv Sci 253(5018):407Google Scholar
  41. 41.
    Abagyan R, Totrov M, Kuznetsov DA (1994) J Comput Chem 15:488CrossRefGoogle Scholar
  42. 42.
    MolSoft (2019) ICM 38 [ICM Program Manual]. MolSoft, San DiegoGoogle Scholar
  43. 43.
    Hajduk PJ, Huth JR, Fesik SW (2005) J Med Chem 48(7):2518PubMedCrossRefGoogle Scholar
  44. 44.
    Simard JR, Grütter C, Pawar V, Aust B, Wolf A, Rabiller M, Wulfert S, Robubi A, Klüter S, Ottmann C, Rauh D (2009) J Am Chem Soc 131(51):18478PubMedCrossRefGoogle Scholar
  45. 45.
    Levinson NM, Kuchment O, Shen K, Young MA, Koldobskiy M, Karplus M, Cole PA, Kuriyan J (2006) PLoS Biol 4(5):144CrossRefGoogle Scholar
  46. 46.
    Iacob RE, Zhang J, Gray NS, Engen JR (2011) PLoS ONE 6(1):e15929PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Zhang J, Adrián FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo G-R, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu G, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS (2010) Nature 463(7280):501PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kornev AP, Taylor SS (2010) Biochim Biophys Acta 1804(3):440PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of CaliforniaSan DiegoUSA

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