Computational Tools for Allosteric Drug Discovery: Site Identification and Focus Library Design

  • Wenkang Huang
  • Ruth NussinovEmail author
  • Jian ZhangEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1529)


Allostery is an intrinsic phenomenon of biological macromolecules involving regulation and/or signal transduction induced by a ligand binding to an allosteric site distinct from a molecule’s active site. Allosteric drugs are currently receiving increased attention in drug discovery because drugs that target allosteric sites can provide important advantages over the corresponding orthosteric drugs including specific subtype selectivity within receptor families. Consequently, targeting allosteric sites, instead of orthosteric sites, can reduce drug-related side effects and toxicity. On the down side, allosteric drug discovery can be more challenging than traditional orthosteric drug discovery due to difficulties associated with determining the locations of allosteric sites and designing drugs based on these sites and the need for the allosteric effects to propagate through the structure, reach the ligand binding site and elicit a conformational change. In this study, we present computational tools ranging from the identification of potential allosteric sites to the design of “allosteric-like” modulator libraries. These tools may be particularly useful for allosteric drug discovery.

Key words

Allosteric site Allosteric modulator Allosteric drug discovery Allostery Allosteric drug design 



This project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. This research was supported [in part] by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by Natural Science Foundation of China (81322046, 81302698, 81473137) and Shanghai Rising-Star Program (13QA1402300).


  1. 1.
    Changeux JP (2013) The concept of allosteric modulation: an overview. Drug Discov Today Technol 10:e223–e228CrossRefPubMedGoogle Scholar
  2. 2.
    Eisenberg D, Marcotte EM, Xenarios I, Yeates TO (2000) Protein function in the post-genomic era. Nature 405:823–826CrossRefPubMedGoogle Scholar
  3. 3.
    Kar G, Keskin O, Gursoy A, Nussinov R (2010) Allostery and population shift in drug discovery. Curr Opin Pharmacol 10:715–722CrossRefPubMedGoogle Scholar
  4. 4.
    Boehr DD, Nussinov R, Wright PE (2009) The role of dynamic conformational ensembles in biomolecular recognition. Nat Chem Biol 5:789–796CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Motlagh HN, Wrabl JO, Li J, Hilser VJ (2014) The ensemble nature of allostery. Nature 508:331–339CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Csermely P, Palotai R, Nussinov R (2010) Induced fit, conformational selection and independent dynamic segments: an extended view of binding events. Trends Biochem Sci 35:539–546CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Sinha N, Nussinov R (2001) Point mutations and sequence variability in proteins: redistributions of preexisting populations. Proc Natl Acad Sci U S A 98:3139–3144CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Goodey NM, Benkovic SJ (2008) Allosteric regulation and catalysis emerge via a common route. Nat Chem Biol 4:474–482CrossRefPubMedGoogle Scholar
  9. 9.
    Nussinov R, Tsai CJ (2013) Allostery in disease and in drug discovery. Cell 153:293–305CrossRefPubMedGoogle Scholar
  10. 10.
    Nussinov R, Tsai CJ (2014) Unraveling structural mechanisms of allosteric drug action. Trends Pharmacol Sci 35:256–264CrossRefPubMedGoogle Scholar
  11. 11.
    Christopoulos A (2002) Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat Rev Drug Discov 1:198–210CrossRefPubMedGoogle Scholar
  12. 12.
    Szilágyi A, Nussinov R, Csermely P (2013) Allo-network drugs: extension of the allosteric drug concept to protein- protein interaction and signaling networks. Curr Top Med Chem 13:64–77CrossRefPubMedGoogle Scholar
  13. 13.
    Cowan-Jacob SW, Jahnke W, Knapp S (2014) Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases. Future Med Chem 6:541–561CrossRefPubMedGoogle Scholar
  14. 14.
    Nussinov R, Tsai C-J (2014) The design of covalent allosteric drugs. Annu Rev Pharmacol Toxicol 55:249–267CrossRefPubMedGoogle Scholar
  15. 15.
    Yang J-S, Seo SW, Jang S et al (2012) Rational engineering of enzyme allosteric regulation through sequence evolution analysis. PLoS Comput Biol 8, e1002612CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ma B, Elkayam T, Wolfson H, Nussinov R (2003) Protein-protein interactions: structurally conserved residues distinguish between binding sites and exposed protein surfaces. Proc Natl Acad Sci U S A 100:5772–5777CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Fang Z, Grütter C, Rauh D (2013) Strategies for the selective regulation of kinases with allosteric modulators: exploiting exclusive structural features. ACS Chem Biol 8:58–70CrossRefPubMedGoogle Scholar
  18. 18.
    Kenakin T, Miller LJ (2010) Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev 62:265–304CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Nussinov R, Tsai C (2012) The different ways through which specificity works in orthosteric and allosteric drugs. Curr Pharm Des 18:1311–1316CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang J, Adrián FJ, Jahnke W et al (2010) Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463:501–506CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Müller CE, Schiedel AC, Baqi Y (2012) Allosteric modulators of rhodopsin-like G protein-coupled receptors: opportunities in drug development. Pharmacol Ther 135:292–315CrossRefPubMedGoogle Scholar
  22. 22.
    Lu S, Li S, Zhang J (2014) Harnessing allostery: a novel approach to drug discovery. Med Res Rev 34:1242–1285CrossRefPubMedGoogle Scholar
  23. 23.
    Lu S, Huang W, Zhang J (2014) Recent computational advances in the identification of allosteric sites in proteins. Drug Discov Today 19:1595–1600CrossRefPubMedGoogle Scholar
  24. 24.
    Li X, Chen Y, Lu S et al (2013) Toward an understanding of the sequence and structural basis of allosteric proteins. J Mol Graph Model 40:30–39CrossRefPubMedGoogle Scholar
  25. 25.
    Wang Q, Zheng M, Huang Z et al (2012) Toward understanding the molecular basis for chemical allosteric modulator design. J Mol Graph Model 38:324–333CrossRefPubMedGoogle Scholar
  26. 26.
    Huang W, Lu S, Huang Z et al (2013) Allosite: a method for predicting allosteric sites. Bioinformatics 29:2357–2359CrossRefPubMedGoogle Scholar
  27. 27.
    Huang Z, Zhu L, Cao Y et al (2011) ASD: a comprehensive database of allosteric proteins and modulators. Nucleic Acids Res 39:D663–D669CrossRefPubMedGoogle Scholar
  28. 28.
    Huang Z, Mou L, Shen Q et al (2014) ASD v2. 0: updated content and novel features focusing on allosteric regulation. Nucleic Acids Res 42:D510–D516CrossRefPubMedGoogle Scholar
  29. 29.
    Le Guilloux V, Schmidtke P, Tuffery P (2009) Fpocket: an open source platform for ligand pocket detection. BMC Bioinformatics 10:168CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Chang C-C, Lin C-J (2011) LIBSVM: a library for support vector machines. ACM Trans Intell Syst Technol 2:27CrossRefGoogle Scholar
  31. 31.
    Bowman GR, Geissler PL (2012) Equilibrium fluctuations of a single folded protein reveal a multitude of potential cryptic allosteric sites. Proc Natl Acad Sci U S A 109:11681–11686CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Jacobs DJ, Livesay DR, Mottonen JM et al (2012) Ensemble properties of network rigidity reveal allosteric mechanisms. Methods Mol Biol 796:279–304CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Villoutreix BO, Kuenemann MA, Poyet J-L et al (2014) Drug-like protein-protein interaction modulators: challenges and opportunities for drug discovery and chemical biology. Mol Inform 33:414–437CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai JiaoTong University School of Medicine (SJTU-SM)ShanghaiChina
  2. 2.Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National LaboratoryNational Cancer InstituteFrederickUSA
  3. 3.Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Sackler Institute of Molecular MedicineTel Aviv UniversityTel AvivIsrael

Personalised recommendations