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Progress in Allosteric Database

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Protein Allostery in Drug Discovery

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1163))

Abstract

An allosteric mechanism refers to the biological regulation process wherein macromolecules propagate the effect of ligand binding at one site to a spatially distant orthosteric locus, thus affecting activity. The theory has remained a trending topic in biology research for over 50 years, since the understanding of allostery is fundamental for gleaning numerous biological processes and developing new drug therapies. In the past two decades, the allosteric paradigm has evolved into more descriptive models, with ever-expanding amounts of experimental data pertaining to newly identified allosteric molecules. The AlloSteric Database (ASD, accessible at http://mdl.shsmu.edu.cn/ASD), which is a comprehensive knowledge repository, has provided the public with integrated information encompassing allosteric proteins, modulators, sites, pathways, and networks to investigate allostery since 2009. In this chapter, we introduce the history and usage of the ASD and give attention to specific applications that have benefited from the ASD.

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References

  1. Alexandrov V, Lehnert U, Echols N, Milburn D, Engelman D, Gerstein M (2005) Normal modes for predicting protein motions: a comprehensive database assessment and associated Web tool. Protein Sci 14(3):633–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Armstrong N, Gouaux E (2000) Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core. Neuron 28(1):165–181

    Article  CAS  PubMed  Google Scholar 

  3. Bian Y, Feng Z, Yang P, Xie XQ (2017) Integrated in silico fragment-based drug design: case study with allosteric modulators on metabotropic glutamate receptor 5. AAPS J 19(4):1235–1248

    Article  CAS  PubMed  Google Scholar 

  4. Changeux JP, Christopoulos A (2016) Allosteric modulation as a unifying mechanism for receptor function and regulation. Cell 166(5):1084–1102

    Article  CAS  PubMed  Google Scholar 

  5. Changeux JP, Edelstein SJ (2005) Allosteric mechanisms of signal transduction. Science 308(5727):1424–1428

    Article  CAS  PubMed  Google Scholar 

  6. Chessari G, Woodhead AJ (2009) From fragment to clinical candidate–a historical perspective. Drug Discov Today 14(13–14):668–675

    Article  CAS  PubMed  Google Scholar 

  7. Congreve M, Oswald C, Marshall FH (2017) Applying structure-based drug design approaches to allosteric modulators of GPCRs. Trends Pharmacol Sci 38(9):837–847

    Article  CAS  PubMed  Google Scholar 

  8. Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237

    Article  CAS  PubMed  Google Scholar 

  9. Cuff AL, Sillitoe I, Lewis T, Redfern OC, Garratt R, Thornton J, Orengo CA (2009) The CATH classification revisited–architectures reviewed and new ways to characterize structural divergence in superfamilies. Nucleic Acids Res 37(Database issue):D310–D314

    Article  CAS  PubMed  Google Scholar 

  10. Davis M, Tobi D (2014) Multiple Gaussian network modes alignment reveals dynamically variable regions: the hemoglobin case. Proteins 82(9):2097–2105

    Article  CAS  PubMed  Google Scholar 

  11. de Kloe GE, Bailey D, Leurs R, de Esch IJ (2009) Transforming fragments into candidates: small becomes big in medicinal chemistry. Drug Discov Today 14(13–14):630–646

    Article  PubMed  Google Scholar 

  12. Dokholyan NV (2016) Controlling allosteric networks in proteins. Chem Rev 116(11):6463–6487

    Article  CAS  PubMed  Google Scholar 

  13. Erman B (2006) The gaussian network model: precise prediction of residue fluctuations and application to binding problems. Biophys J 91(10):3589–3599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Feher VA, Durrant JD, Van Wart AT, Amaro RE (2014) Computational approaches to mapping allosteric pathways. Curr Opin Struct Biol 25:98–103

    Article  CAS  PubMed  Google Scholar 

  15. Fischer S, Olsen KW, Nam K, Karplus M (2011) Unsuspected pathway of the allosteric transition in hemoglobin. Proc Natl Acad Sci U S A 108(14):5608–5613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Goodey NM, Benkovic SJ (2008) Allosteric regulation and catalysis emerge via a common route. Nat Chem Biol 4(8):474–482

    Article  CAS  PubMed  Google Scholar 

  17. Gregory KJ, Dong EN, Meiler J, Conn PJ (2011) Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential. Neuropharmacology 60(1):66–81

    Article  CAS  PubMed  Google Scholar 

  18. Huang Z, Zhu L, Cao Y, Wu G, Liu X, Chen Y, Wang Q, Shi T, Zhao Y, Wang Y, Li W, Li Y, Chen H, Chen G, Zhang J (2011) ASD: a comprehensive database of allosteric proteins and modulators. Nucleic Acids Res 39(Database issue):D663–D669

    Article  CAS  PubMed  Google Scholar 

  19. Huang Z, Mou L, Shen Q, Lu S, Li C, Liu X, Wang G, Li S, Geng L, Liu Y, Wu J, Chen G, Zhang J (2014) ASD v2.0: updated content and novel features focusing on allosteric regulation. Nucleic Acids Res 42(Database issue):D510–D516

    Article  CAS  PubMed  Google Scholar 

  20. Huang M, Song K, Liu X, Lu S, Shen Q, Wang R, Gao J, Hong Y, Li Q, Ni D, Xu J, Chen G, Zhang J (2018) AlloFinder: a strategy for allosteric modulator discovery and allosterome analyses. Nucleic Acids Res 46(W1):W451–W458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jiang L, Zhang X, Chen X, He Y, Qiao L, Zhang Y, Li G, Xiang Y (2015) Virtual screening and molecular dynamics study of potential negative allosteric modulators of mGluR1 from Chinese herbs. Molecules 20(7):12769–12786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Johnstone S, Albert JS (2017) Pharmacological property optimization for allosteric ligands: a medicinal chemistry perspective. Bioorg Med Chem Lett 27(11):2239–2258

    Article  CAS  PubMed  Google Scholar 

  23. Joseph-McCarthy D, Campbell AJ, Kern G, Moustakas D (2014) Fragment-based lead discovery and design. J Chem Inf Model 54(3):693–704. https://doi.org/10.1021/ci400731w

    Article  CAS  PubMed  Google Scholar 

  24. Kew JN, Kemp JA (2005) Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology 179(1):4–29

    Article  CAS  PubMed  Google Scholar 

  25. Koshland DE Jr, Nemethy G, Filmer D (1966) Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry 5(1):365–385

    Article  CAS  PubMed  Google Scholar 

  26. Kumar A, Voet A, Zhang KY (2012) Fragment based drug design: from experimental to computational approaches. Curr Med Chem 19(30):5128–5147

    Article  CAS  PubMed  Google Scholar 

  27. Leach AR, Gillet VJ, Lewis RA, Taylor R (2010) Three-dimensional pharmacophore methods in drug discovery. J Med Chem 53(2):539–558

    Article  CAS  PubMed  Google Scholar 

  28. Li H, Chang YY, Yang LW, Bahar I (2016) iGNM 2.0: the Gaussian network model database for biomolecular structural dynamics. Nucleic Acids Res 44(D1):D415–D422

    Article  CAS  PubMed  Google Scholar 

  29. Lindsley CW, Emmitte KA, Hopkins CR, Bridges TM, Gregory KJ, Niswender CM, Conn PJ (2016) Practical strategies and concepts in GPCR allosteric modulator discovery: recent advances with metabotropic glutamate receptors. Chem Rev 116(11):6707–6741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu Y, Bahar I (2010) Toward understanding allosteric signaling mechanisms in the ATPase domain of molecular chaperones. Pac Symp Biocomput 2010:269–280

    Google Scholar 

  31. Lu S, Zhang J (2018) Small molecule allosteric modulators of G-protein-coupled receptors: drug-target interactions. J Med Chem 62(1):24–45. https://doi.org/10.1021/acs.jmedchem.7b01844

    Article  CAS  PubMed  Google Scholar 

  32. Lu S, Huang W, Zhang J (2014a) Recent computational advances in the identification of allosteric sites in proteins. Drug Discov Today 19(10):1595–1600

    Article  CAS  PubMed  Google Scholar 

  33. Lu S, Li S, Zhang J (2014b) Harnessing allostery: a novel approach to drug discovery. Med Res Rev 34(6):1242–1285

    Article  CAS  PubMed  Google Scholar 

  34. Lu S, Jang H, Muratcioglu S, Gursoy A, Keskin O, Nussinov R, Zhang J (2016) Ras conformational ensembles, allostery, and signaling. Chem Rev 116(11):6607–6665

    Article  CAS  PubMed  Google Scholar 

  35. Monod J, Wyman J, Changeux JP (1965) On the nature of allosteric transitions: a plausible model. J Mol Biol 12:88–118

    Article  CAS  PubMed  Google Scholar 

  36. Motlagh HN, Wrabl JO, Li J, Hilser VJ (2014) The ensemble nature of allostery. Nature 508(7496):331–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Murray CW, Rees DC (2009) The rise of fragment-based drug discovery. Nat Chem 1(3):187–192

    Article  CAS  PubMed  Google Scholar 

  38. Murzin AG, Brenner SE, Hubbard T, Chothia C (1995) SCOP: a structural classification of proteins database for the investigation of sequences and structures. J Mol Biol 247(4):536–540

    CAS  PubMed  Google Scholar 

  39. Nussinov R (2016) Introduction to protein ensembles and allostery. Chem Rev 116(11):6263–6266

    Article  PubMed  CAS  Google Scholar 

  40. Nussinov R, Tsai CJ (2013) Allostery in disease and in drug discovery. Cell 153(2):293–305

    Article  CAS  PubMed  Google Scholar 

  41. Nussinov R, Tsai CJ (2014) Unraveling structural mechanisms of allosteric drug action. Trends Pharmacol Sci 35(5):256–264

    Article  CAS  PubMed  Google Scholar 

  42. Nussinov R, Tsai CJ (2015) The design of covalent allosteric drugs. Annu Rev Pharmacol Toxicol 55:249–267

    Article  CAS  PubMed  Google Scholar 

  43. Nussinov R, Ma B, Tsai CJ, Csermely P (2013) Allosteric conformational barcodes direct signaling in the cell. Structure 21(9):1509–1521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM (2013) K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503(7477):548–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Perutz MF, Rossmann MG, Cullis AF, Muirhead H, Will G, North AC (1960) Structure of haemoglobin: a three-dimensional Fourier synthesis at 5.5-A. resolution, obtained by X-ray analysis. Nature 185(4711):416–422

    Article  CAS  PubMed  Google Scholar 

  46. Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5(4):725–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schumacher MA, Zheleznova EE, Poundstone KS, Kluger R, Jones RT, Brennan RG (1997) Allosteric intermediates indicate R2 is the liganded hemoglobin end state. Proc Natl Acad Sci U S A 94(15):7841–7844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Seidel T, Ibis G, Bendix F, Wolber G (2010) Strategies for 3D pharmacophore-based virtual screening. Drug Discov Today Technol 7(4):e203–e270

    Article  CAS  Google Scholar 

  49. Shen Q, Wang G, Li S, Liu X, Lu S, Chen Z, Song K, Yan J, Geng L, Huang Z, Huang W, Chen G, Zhang J (2016) ASD v3.0: unraveling allosteric regulation with structural mechanisms and biological networks. Nucleic Acids Res 44(D1):D527–D535

    Article  CAS  PubMed  Google Scholar 

  50. Shibayama N, Sugiyama K, Tame JR, Park SY (2014) Capturing the hemoglobin allosteric transition in a single crystal form. J Am Chem Soc 136(13):5097–5105

    Article  CAS  PubMed  Google Scholar 

  51. Silva MM, Rogers PH, Arnone A (1992) A third quaternary structure of human hemoglobin A at 1.7-A resolution. J Biol Chem 267(24):17248–17256

    CAS  PubMed  Google Scholar 

  52. Smith RD, Lu J, Carlson HA (2017) Are there physicochemical differences between allosteric and competitive ligands? PLoS Comput Biol 13(11):e1005813

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Tobi D (2016) Dynamics and allostery of the ionotropic glutamate receptors and the ligand binding domain. Proteins 84(2):267–277

    Article  CAS  PubMed  Google Scholar 

  54. van Westen GJ, Gaulton A, Overington JP (2014) Chemical, target, and bioactive properties of allosteric modulation. PLoS Comput Biol 10(4):e1003559

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Wagner JR, Lee CT, Durrant JD, Malmstrom RD, Feher VA, Amaro RE (2016) Emerging computational methods for the rational discovery of allosteric drugs. Chem Rev 116(11):6370–6390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang Q, Zheng M, Huang Z, Liu X, Zhou H, Chen Y, Shi T, Zhang J (2012) Toward understanding the molecular basis for chemical allosteric modulator design. J Mol Graph Model 38:324–333

    Article  CAS  PubMed  Google Scholar 

  57. Wenthur CJ, Gentry PR, Mathews TP, Lindsley CW (2014) Drugs for allosteric sites on receptors. Annu Rev Pharmacol Toxicol 54:165–184

    Article  CAS  PubMed  Google Scholar 

  58. Williams G (2010) Elastic network model of allosteric regulation in protein kinase PDK1. BMC Struct Biol 10:11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Wootten D, Christopoulos A, Sexton PM (2013) Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov 12(8):630–644

    Article  CAS  PubMed  Google Scholar 

  60. Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, Niswender CM, Katritch V, Meiler J, Cherezov V, Conn PJ, Stevens RC (2014) Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 344(6179):58–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yang SY (2010) Pharmacophore modeling and applications in drug discovery: challenges and recent advances. Drug Discov Today 15(11–12):444–450

    Article  CAS  PubMed  Google Scholar 

  62. Yelshanskaya MV, Li M, Sobolevsky AI (2014) Structure of an agonist-bound ionotropic glutamate receptor. Science 345(6200):1070–1074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhu S, Gouaux E (2017) Structure and symmetry inform gating principles of ionotropic glutamate receptors. Neuropharmacology 112(Pt A):11–15

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    Kun Song, Jian Zhang & Shaoyong Lu

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  1. Kun Song
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  2. Jian Zhang
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  3. Shaoyong Lu
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Editors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    Jian Zhang

  2. Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA, Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ruth Nussinov

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Song, K., Zhang, J., Lu, S. (2019). Progress in Allosteric Database. In: Zhang, J., Nussinov, R. (eds) Protein Allostery in Drug Discovery. Advances in Experimental Medicine and Biology, vol 1163. Springer, Singapore. https://doi.org/10.1007/978-981-13-8719-7_4

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