Finding Potential Multitarget Ligands Using PubChem

  • Sunghwan KimEmail author
  • Benjamin A. Shoemaker
  • Evan E. Bolton
  • Stephen H. Bryant
Part of the Methods in Molecular Biology book series (MIMB, volume 1825)


PubChem ( is a key chemical information resource, developed and maintained by the US National Institutes of Health. The present chapter describes how to find potential multitarget ligands from PubChem that would be tested in further experiments. While the protocol presented here uses PubChem’s Web-based interfaces to allow users to follow it interactively, it can also be implemented in computer software by using programmatic access interfaces to PubChem (such as PUG-REST or E-Utilities).

Key words

PubChem Multitarget ligand Virtual screening FLink Entrez PUG-REST E-Utilities 



This work was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health, US Department of Health and Human Services. We would like to thank Douglas Joubert, NIH Library Editing Service, for reviewing the manuscript.


  1. 1.
    Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J, Yu B, Zhang J, Bryant SH (2016) PubChem substance and compound databases. Nucleic Acids Res 44(D1):D1202–D1213. Scholar
  2. 2.
    Wang YL, Suzek T, Zhang J, Wang JY, He SQ, Cheng TJ, Shoemaker BA, Gindulyte A, Bryant SH (2014) PubChem BioAssay: 2014 update. Nucleic Acids Res 42(D1):D1075–D1082. Scholar
  3. 3.
    Kim S (2016) Getting the most out of PubChem for virtual screening. Expert Opin Drug Discov 11(9):843–855. Scholar
  4. 4.
    Johnson MA, Maggiora GM (eds) (1990) Concepts and applications of molecular similarity. John Wiley & Sons, Inc., New York, NYGoogle Scholar
  5. 5.
    Pietras K, Sjoblom T, Rubin K, Heldin CH, Ostman A (2003) PDGF receptors as cancer drug targets. Cancer Cell 3(5):439–443. Scholar
  6. 6.
    Board R, Jayson GC (2005) Platelet-derived growth factor receptor (PDGFR): a target for anticancer therapeutics. Drug Resist Update 8(1–2):75–83. Scholar
  7. 7.
    Traxler P (2003) Tyrosine kinases as targets in cancer therapy–successes and failures. Expert Opin Ther Targets 7(2):215–234. Scholar
  8. 8.
    Roskoski R (2007) Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun 356(2):323–328. Scholar
  9. 9.
    Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8(8):579–591. Scholar
  10. 10.
    Takahashi S (2011) Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull 34(12):1785–1788CrossRefGoogle Scholar
  11. 11.
    Kim S, Thiessen PA, Bolton EE, Bryant SH (2015) PUG-SOAP and PUG-REST: web services for programmatic access to chemical information in PubChem. Nucleic Acids Res 43(W1):W605–W611. Scholar
  12. 12.
    Schuler GD, Epstein JA, Ohkawa H, Kans JA (1996) Entrez: molecular biology database and retrieval system. Methods Enzymol 266:141–162. Scholar
  13. 13.
    McEntyre J (1998) Linking up with Entrez. Trends Gene 14(1):39–40. Scholar
  14. 14.
    Entrez Help (2005) National Center for Biotechnology Information (US).
  15. 15.
    Agarwala R, Barrett T, Beck J, Benson DA, Bollin C, Bolton E, Bourexis D, Brister JR, Bryant SH, Lanese K, Charowhas C, Clark K, DiCuccio M, Dondoshansky I, Federhen S, Feolo M, Funk K, Geer LY, Gorelenkov V, Hoeppner M, Holmes B, Johnson M, Khotomlianski V, Kimchi A, Kimelman M, Kitts P, Klimke W, Krasnov S, Kuznetsov A, Landrum MJ, Landsman D, Lee JM, Lipman DJ, Lu ZY, Madden TL, Madcj T, Marchler-Bauer A, Karsch-Mizrachi I, Murphy T, Orris R, Ostell J, O'Sullivan C, Panchenko A, Phan L, Preuss D, Pruitt KD, Rodarmer K, Rubinstein W, Sayers EW, Schneider V, Schuler GD, Sherry ST, Sirotkin K, Siyan K, Slotta D, Soboleva A, Soussov V, Starchenko G, Tatusova TA, Todorov K, Trawick BW, Vakatov D, Wang YL, Ward M, Wilbur WJ, Yaschenko E, Zbicz K, Coordinators NR (2016) Database resources of the national center for biotechnology information. Nucleic Acids Res 44(D1):D7–D19. Scholar
  16. 16.
    FLink (2010) Frequency weighted links. National Center for Biotechnology Information, National Library of Medicine.
  17. 17.
    Dalby A, Nourse JG, Hounshell WD, Gushurst AKI, Grier DL, Leland BA, Laufer J (1992) Description of several chemical-structure file formats used by computer-programs developed at molecular design limited. J Chem Inf Comput Sci 32(3):244–255. Scholar
  18. 18.
    Weininger D (1988) Smiles, a chemical language and information-system .1. Introduction to methodology and encoding rules. J Chem Inf Comput Sci 28(1):31–36. Scholar
  19. 19.
    Weininger D, Weininger A, Weininger JL (1989) Smiles .2. Algorithm for generation of unique smiles notation. J Chem Inf Comput Sci 29(2):97–101. Scholar
  20. 20.
    Weininger D (1990) Smiles .3. Depict–graphical depiction of chemical structures. J Chem Inf Comput Sci 30(3):237–243. Scholar
  21. 21.
    Heller S, McNaught A, Stein S, Tchekhovskoi D, Pletnev I (2013) InChI–the worldwide chemical structure identifier standard. J Cheminform 5:7. Scholar
  22. 22.
    Heller S, McNaught A, Pletnev I, Stein S, Tchekhovskoi D (2015) InChI, the IUPAC international chemical identifier. J Cheminform 7:23. Scholar
  23. 23.
    Bender A, Glen RC (2004) Molecular similarity: a key technique in molecular informatics. Org Biomol Chem 2(22):3204–3218. Scholar
  24. 24.
    Maldonado AG, Doucet JP, Petitjean M, Fan BT (2006) Molecular similarity and diversity in chemoinformatics: from theory to applications. Mol Divers 10(1):39–79. Scholar
  25. 25.
    Eckert H, Bojorath J (2007) Molecular similarity analysis in virtual screening: foundations, limitations and novel approaches. Drug Discov Today 12(5–6):225–233. Scholar
  26. 26.
    Willett P (2014) The calculation of molecular structural similarity: principles and practice. Mol Inf 33(6–7):403–413. Scholar
  27. 27.
    Koutsoukas A, Paricharak S, Galloway W, Spring DR, Ijzerman AP, Glen RC, Marcus D, Bender A (2014) How diverse are diversity assessment methods? A comparative analysis and benchmarking of molecular descriptor space. J Chem Inf Model 54(1):230–242. Scholar
  28. 28.
    Sheridan RP, Kearsley SK (2002) Why do we need so many chemical similarity search methods? Drug Discov Today 7(17):903–911. Scholar
  29. 29.
    Kim S, Bolton EE, Bryant SH (2016) Similar compounds versus similar conformers: complementarity between PubChem 2-D and 3-D neighboring sets. J Cheminform 8:62. Scholar
  30. 30.
    Bolton EE, Kim S, Bryant SH (2011) PubChem3D: similar conformers. J Cheminform 3:13. Scholar
  31. 31.
    Bolton EE, Chen J, Kim S, Han LY, He SQ, Shi WY, Simonyan V, Sun Y, Thiessen PA, Wang JY, Yu B, Zhang J, Bryant SH (2011) PubChem3D: a new resource for scientists. J Cheminform 3:32. Scholar
  32. 32.
    Kim S, Bolton EE, Bryant SH (2011) PubChem3D: biologically relevant 3-D similarity. J Cheminform 3:26. Scholar
  33. 33.
    Kim S, Bolton EE, Bryant SH (2012) Effects of multiple conformers per compound upon 3-D similarity search and bioassay data analysis. J Cheminform 4:28. Scholar
  34. 34.
    Kim S, Han LY, Yu B, Hahnke VD, Bolton EE, Bryant SH (2015) PubChem structure-activity relationship (SAR) clusters. J Cheminform 7:33. Scholar
  35. 35.
  36. 36.
    Chen X, Reynolds CH (2002) Performance of similarity measures in 2D fragment-based similarity searching: comparison of structural descriptors and similarity coefficients. J Chem Inf Comput Sci 42(6):1407–1414. Scholar
  37. 37.
    Holliday JD, Salim N, Whittle M, Willett P (2003) Analysis and display of the size dependence of chemical similarity coefficients. J Chem Inf Comput Sci 43(3):819–828. Scholar
  38. 38.
    Holliday JD, Hu CY, Willett P (2002) Grouping of coefficients for the calculation of inter-molecular similarity and dissimilarity using 2D fragment bit-strings. Comb Chem High Throughput Screen 5(2):155–166CrossRefGoogle Scholar
  39. 39.
    Grant JA, Pickup BT (1995) A Gaussian description of molecular shape. J Phys Chem 99(11):3503–3510CrossRefGoogle Scholar
  40. 40.
    Grant JA, Gallardo MA, Pickup BT (1996) A fast method of molecular shape comparison: a simple application of a Gaussian description of molecular shape. J Comput Chem 17(14):1653–1666CrossRefGoogle Scholar
  41. 41.
    Grant JA, Pickup BT (1996) A Gaussian description of molecular shape (vol 99, pg 3505, 1995). J Phys Chem 100(6):2456–2456CrossRefGoogle Scholar
  42. 42.
    Grant JA, Pickup BT (1997) Gaussian shape methods. In: van Gunsteren WF, Weiner PK, Wilkinson AJ (eds) Computer simulation of biomolecular systems. Kluwer Academic Publishers, Dordrecht, pp 150–176CrossRefGoogle Scholar
  43. 43.
    Rush TS, Grant JA, Mosyak L, Nicholls A (2005) A shape-based 3-D scaffold hopping method and its application to a bacterial protein-protein interaction. J Med Chem 48(5):1489–1495. Scholar
  44. 44.
    ROCS–rapid overlay of chemical structures (2010) 3.1.0 edn. OpenEye Scientific Software, Inc., Santa Fe, NMGoogle Scholar
  45. 45.
    ShapeTK–C++ (2010) 1.8.0 edn. OpenEye Scientific Software, Inc., Santa Fe, NMGoogle Scholar
  46. 46.
    Bolton EE, Kim S, Bryant SH (2011) PubChem3D: conformer generation. J Cheminform 3:4. Scholar
  47. 47.
    Kim S, Bolton EE, Bryant SH (2013) PubChem3D: conformer ensemble accuracy. J Cheminform 5(1). Scholar
  48. 48.
    Borodina YV, Bolton E, Fontaine F, Bryant SH (2007) Assessment of conformational ensemble sizes necessary for specific resolutions of coverage of conformational space. J Chem Inf Model 47(4):1428–1437. Scholar
  49. 49.
    Fu G, Batchelor C, Dumontier M, Hastings J, Willighagen E, Bolton E (2015) PubChemRDF: towards the semantic annotation of PubChem compound and substance databases. J Cheminform 7:34. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Sunghwan Kim
    • 1
    Email author
  • Benjamin A. Shoemaker
    • 1
  • Evan E. Bolton
    • 1
  • Stephen H. Bryant
    • 1
  1. 1.Department of Health and Human Services, National Center for Biotechnology InformationNational Library of Medicine, National Institutes of HealthBethesdaUSA

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