Druggability of intrinsically disordered proteins

Advances in Experimental Medicine and Biology

Volumn 870, Issue , 2015, Pages 383-400

  Joshi, Priyanka ^a   Vendruscolo, Michele ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

Drug design; Drug discovery; Intrinsically disordered proteins; Nuclear magnetic resonance spectroscopy; Small molecule library

Indexed keywords

AMYLOID BETA PROTEIN; INTRINSICALLY DISORDERED PROTEIN; MAX PROTEIN; MYC PROTEIN; PROTEIN MDM2; PROTEIN P53;

ALLOSTERISM; BIOINFORMATICS; CHEMICAL REACTION KINETICS; CHEMOINFORMATICS; DRUG DESIGN; FRAGMENT BASED DRUG DESIGN; HUMAN; MOLECULAR DYNAMICS; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; PROTEIN STABILITY; PROTEIN TARGETING; PROTON NUCLEAR MAGNETIC RESONANCE; X RAY CRYSTALLOGRAPHY; CHEMISTRY; DRUG EFFECTS; NUCLEAR MAGNETIC RESONANCE; SMALL ANGLE SCATTERING; X RAY DIFFRACTION;

MOLECULAR DYNAMICS; MOLECULES; NUCLEAR MAGNETIC RESONANCE; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; X RAY SCATTERING;

DRUG DESIGN; DRUG DISCOVERY; INTRINSICALLY DISORDERED PROTEINS; MOLECULAR DYNAMICS SIMULATIONS; NUCLEAR MAGNETIC RESONANCE (NMR); SMALL-MOLECULE LIBRARY; THERAPEUTIC INTERVENTION; THREE-DIMENSIONAL STRUCTURE;

PROTEINS;

DRUG DESIGN; INTRINSICALLY DISORDERED PROTEINS; NUCLEAR MAGNETIC RESONANCE, BIOMOLECULAR; SCATTERING, SMALL ANGLE; X-RAY DIFFRACTION;

EID: 84942155226     PISSN: 00652598     EISSN: 22148019     Source Type: Book Series    
DOI: 10.1007/978-3-319-20164-1_13     Document Type: Chapter

References (83)

1. Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov 3(4):301–317
2. Arosio P, Vendruscolo M, Dobson CM et al (2014) Chemical kinetics for drug discovery to combat protein aggregation diseases. Trends Pharmacol Sci 35(3):127–135
3. Babu MM, Kriwacki RW, Pappu RV (2012) Versatility from protein disorder. Science 337(6101):1460–1461
4. Bernadό P, Svergun DI (2012) Structural analysis of intrinsically disordered proteins by smallangle X-ray scattering. Mol BioSys 8(1):151–167
5. Bernadó P, Mylonas E, Petoukhov MV et al (2007) Structural characterization of flexible proteins using small-angle X-ray scattering. J Am Chem Soc 129(17):5656–5664
6. Blackwood EM, Eisenman RN (1991) Max: a helix-loop-helix zipper protein that forms a sequence- specific DNA-binding complex with Myc. Science 251(4998):1211–1217
7. Blobel J, Bernadό P, Svergun DI et al (2009) Low-resolution structures of transient protein-protein complexes using small-angle X-ray scattering. J Am Chem Soc 131(12):4378–4386
8. Chène P (2004) Inhibition of the p53-MDM2 interaction: targeting a protein-protein interface. Mol Cancer Res 2(1):20–28
9. Cheng Y, LeGall T, Oldfield CJ et al (2006) Rational drug design via intrinsically disordered protein. Trends Biotechnol 24(10):435–442
10. Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366
11. Clackson T, Well JA (1995) A hotspot of binding energy in a hormone-receptor interface. Science 267(5196):383–386
12. Cohen SIA, Linse S, Luheshi LM et al (2013) Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proc Natl Acad Sci U S A 110(24):9758–9763
13. Congreve M, Chessari G, Tisi D et al (2008) Recent developments in fragment-based drug discovery. J Med Chem 51(13):3661–3680
14. Conte LL, Chothia C, Janin J (1999) The atomic structure of protein-protein recognition sites. J Mol Biol 285(5):2177–2198
15. Dang CV (1999) c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 19(1):1–11
16. Dawson R, Müller L, Dehner A et al (2003) The N-terminal domain of p53 is natively unfolded. J Mol Biol 332(5):1131–1141
17. Dobson CM (2001) The structural basis of protein folding and its links with human disease. Philos Trans R Soc B 356(1406):133–145
18. Dobson CM (2004) Chemical space and biology. Nature 432(7019):824–828
19. Dunker AK, Uversky VN (2010) Drugs for ‘protein clouds’: targeting intrinsically disordered transcription factors. Curr Op Pharmacol 10(6):782–788
20. Dunker AK, Brown CJ, Lawson JD et al (2002) Intrinsic disorder and protein function. Biochemistry 41(21):6573–6582
21. Dunker AK, Cortese MS, Romero P et al (2005) Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J 272(20):5129–5148
22. Dyson HJ, Wright PE (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6(3):197–208
23. Eisenberg D, Jucker M (2012) The amyloid state of proteins in human diseases. Cell 148(6):1188–1203
24. Fitzpatrick AWP, Debelouchina GT, Bayro MJ et al (2013) Atomic structure and hierarchical assembly of a cross-β amyloid fibril. Proc Natl Acad Sci U S A 110(14):5468–5473
25. Fry DC, Wartchow C, Graves B et al (2013) Deconstruction of a nutlin: dissecting the binding determinants of a potent protein-protein interaction inhibitor. ACS Med Chem Lett 4(7):660–665
26. Gaulton A, Bellis LJ, Bento AP et al (2012) ChEMBL: a large-scale bioactivity database for drug discovery. Nucl Acids Res 40(Database issue):D1100–D1107
27. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol 8(2):101–112
28. Habchi J, Tompa P, Longhi S et al (2014) Introducing protein intrinsic disorder. Chem Rev 114(13):6561–6588
29. Hajduk PJ, Greer J (2007) A decade of fragment-based drug design: strategic advances and lessons learned. Nat Rev Drug Discov 6(3):211–219
30. Hajduk PJ, Meadows RP, Fesik SW (1999) NMR-based screening in drug discovery. Q Rev Bioph 32(03):211–240
31. Hammoudeh DI, Follis AV, Prochownik EV et al (2009) Multiple independent binding sites for small-molecule inhibitors on the oncoprotein c-Myc. J Am Chem Soc 131(21):7390–7401
32. Harvey SR, Porrini M, Stachl C et al (2012) Small-molecule inhibition of c-MYC: MAX leucine zipper formation is revealed by ion mobility mass spectrometry. J Am Chem Soc 134(47):19384–19392
33. Hawkes CA, Ng V, McLaurin J (2009) Small molecule inhibitors of Aβ aggregation and neurotoxicity. Drug Develop Res 70(2):111–124
34. Hopkins AL, Groom CR (2002) The druggable genome. Nat Rev Drug Discov 1(9):727–730
35. Iakoucheva LM, Brown CJ, Lawson JD et al (2002) Intrinsic disorder in cell-signaling and cancerassociated proteins. J Mol Biol 323(3):573–584
36. Imming P, Sinning C, Meyer A (2006) Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov 5:821–834
37. Irwin JJ, Shoichet BK (2004) ZINC—a free database of commercially available compounds for virtual screening. J Chem Inf Model 45(1):177–182
38. Ivetac A, McCammon JA (2012) A molecular dynamics ensemble-based approach for the mapping of druggable binding sites. In: Baron R (ed) Computational drug discovery and design, vol 819. Methods in molecular biology. Springer New York, New York, pp 3–12
39. Jones S, Thornton JM (1996) Principles of protein-protein interactions. Proc Natl Acad Sci U S A 93(1):13–20
40. Klages J, Coles M, Kessler H (2007) NMR-based screening: a powerful tool in fragment-based drug discovery. Analyst 132(7):692
41. Knowles TP, Waudby CA, Devlin GL et al (2009) An analytical solution to the kinetics of breakable filament assembly. Science 326(5959):1533–1537
42. Knowles TP, Vendruscolo M, Dobson CM (2014) The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol 15(6):384–396
43. Kozakov D, Hall DR, Chuang GY et al (2011) Structural conservation of druggable hotspots in protein-protein interfaces. Proc Natl Acad Sci U S A 108(33):13528–13533
44. Kubbutat MH, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387(6630):299–303
45. Lipinski CA (2004) Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today 1(4):337–341
46. Malaney P, Pathak RR, Xue B et al (2013) Intrinsic disorder in PTEN and its interactome confers structural plasticity and functional versatility. Sci Rep 3:2035
47. McKoy AF, Chen J, Schupbach T et al (2012) A novel inhibitor of amyloid β (Aβ) peptide aggregation: from high throughput screening to efficacy in an animal model of Alzheimer disease. J Biol Chem 287(46):38992–39000
48. Meisl G, Yang X, Hellstrand E et al (2014) Differences in nucleation behavior underlie the contrasting aggregation kinetics of the Aβ40 and Aβ42 peptides. Proc Natl Acad Sci U S A 111(26):9384–9389
49. Mészáros B, Simon I, Dosztányi Z (2011) The expanding view of protein–protein interactions: complexes involving intrinsically disordered proteins. Phys Biol 8(3):035003
50. Metallo SJ (2010) Intrinsically disordered proteins are potential drug targets. Curr Op Chem Biol 14(4):481–488
51. Michel J, Cuchillo R (2012) The impact of small molecule binding on the energy landscape of the intrinsically disordered protein c-Myc. PloS ONE 7(7):e41070
52. Michelsen K, Jordan JB, Lewis J et al (2012) Ordering of the N-terminus of human MDM2 by small molecule inhibitors. J Am Chem Soc 134(41):17059–17067
53. Muller PA, Vousden KH (2014) Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25(3):304–317
54. Murray CW, Blundell TL (2010) Structural biology in fragment-based drug design. Curr Op Struct Biol 20(4):497–507
55. Murray CW, Rees DC (2009) The rise of fragment-based drug discovery. Nat Chem 1(3):187–192
56. Necula M, Kayed R, Milton S et al (2007) Small molecule inhibitors of aggregation indicate that amyloid beta oligomerization and fibrillization pathways are independent and distinct. J Biol Chem 282(14):10311–10324
57. Oldfield CJ, Meng J, Yang JY et al (2008) Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners. BMC Genomics 9(Suppl 1):S1
58. Pellecchia M, Sem DS, Wuthrich K (2002) NMR in drug discovery. Nat Rev Drug Discov 1(3):211–219
59. Pellecchia M, Bertini I, Cowburn D et al (2008) Perspectives on NMR in drug discovery: a technique comes of age. Nat Rev Drug Discov 7(9):738–745
60. Porat Y, Abramowitz A, Gazit E (2006) Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des 67(1):27–37
61. Renaud JP, Delsuc MA (2009) Biophysical techniques for ligand screening and drug design. Curr Op Pharmacol 9(5):622–628
62. Rezaei-Ghaleh N, Blackledge M, Zweckstetter M (2012) Intrinsically disordered proteins: from sequence and conformational properties toward drug discovery. ChemBioChem 13(7):930–950
63. Shuker SB, Hajduk PJ, Meadows RP et al (1996) Discovering high-affinity ligands for proteins: SAR by NMR. Science 274(5292):1531–1534
64. Sun C, Petros AM, Hajduk PJ (2011) Fragment-based lead discovery: challenges and opportunities. J Comput-Aided Mol Des 25(7):607–610
65. Tompa P (2012) Intrinsically disordered proteins: a 10-year recap. Trends Biochem Sci 37(12):509–516
66. Toth G, Gardai SJ, Zago W et al (2014) Targeting the intrinsically disordered structural ensemble of α-synuclein by small molecules as a potential therapeutic strategy for Parkinson’s disease. PloS ONE 9(2):e87133
67. Uversky VN (2012) Intrinsically disordered proteins and novel strategies for drug discovery. Expert Opin Drug Discov 7(6):475–488
68. Uversky VN (2013) Unusual biophysics of intrinsically disordered proteins. Biochim Bioph Acta 1834(5):932–951
69. Uversky VN, Oldfield CJ, Dunker AK (2008) Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Bioph 37:215–246
70. Uversky VN, Oldfield CJ, Midic U et al (2009) Unfoldomics of human diseases: linking protein intrinsic disorder with diseases. BMC Genomics 10(Suppl 1):S7
71. van der Lee R, Buljan M, Lang B et al (2014) Classification of intrinsically disordered regions and proteins. Chem Rev 114:6589–6631
72. Varadi M, Kosol S, Lebrun P et al (2014) pE-DB: a database of structural ensembles of intrinsically disordered and of unfolded proteins. Nucl Acids Res 42(D1):D326–D335
73. Vendruscolo M (2007) Determination of conformationally heterogeneous states of proteins. Curr Op Struct Biol 17(1):15–20
74. Vendruscolo M, Dobson CM (2005) Towards complete descriptions of the free–energy landscapes of proteins. Philos Trans R Soc, A 363(1827):433–452
75. Wang Y, Xiao J, Suzek TO et al (2009) PubChem: a public information system for analyzing bioactivities of small molecules. Nucl Acids Res 37(suppl 2):W623–W633
76. Wang J, Cao Z, Zhao L et al (2011) Novel strategies for drug discovery based on Intrinsically Disordered Proteins (IDPs). Int J Mol Sci 12(5):3205–3219
77. Wang Q, Liang G, Zhang M et al (2014) De novo design of self-assembled hexapeptides as β-Amyloid (Aβ) peptide inhibitors. ACS Chem Neurosci 5(10):972–81
78. Warr WA (2009) Fragment-based drug discovery. J Comput-Aided Mol Des 23(8):453–458
79. Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at proteinprotein interfaces. Nature 450(7172):1001–1009
80. Welsch ME, Snyder SA, Stockwell BR (2010) Privileged scaffolds for library design and drug discovery. Curr Op Chem Biol 14(3):347–361
81. Wishart DS, Knox C, Guo AC et al (2006) DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucl Acids Res 34(Database issue):D668–D672
82. Yamin G, Ruchala P, Teplow DB (2009) A peptide hairpin inhibitor of amyloid beta-protein oligomerization and fibrillogenesis. BioChemistry 48(48):11329–11331
83. Zhu M, De Simone A, Schenk D et al (2013) Identification of small-molecule binding pockets in the soluble monomeric form of the Aβ42 peptide. J Chem Phys 139(3):035101