Abstract
While protein-protein interfaces have promised a range of benefits over conventional sites in drug discovery, they present unique challenges. Here we describe recent developments that facilitate many aspects of the drug discovery process – including characterization and classification of interfaces, identifying druggable sites and strategies for inhibitor development.
Keywords
- Alanine Scanning
- Secondary Receptor
- Synthetic Small Molecule
- Computational Alanine Scanning
- NHEJ Protein
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Lipinski CA, Lombardo F, Dominy BW et al (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26
Blundell T, Sibanda BL, Pearl L (1983) Three-dimensional structure, specificity and catalytic mechanism of renin. Nature 304:273–275
Foundling SI, Cooper J, Watson FE et al (1987) High resolution X-ray analyses of renin inhibitor-aspartic proteinase complexes. Nature 327:349–352
Lapatto R, Blundell T, Hemmings A et al (1989) X-ray analysis of HIV-1 proteinase at 2.7 A resolution confirms structural homology among retroviral enzymes. Nature 342:299–302
Dhanaraj V, Dealwis CG, Frazao C et al (1992) X-ray analyses of peptide-inhibitor complexes define the structural basis of specificity for human and mouse renins. Nature 357:466–472
Albiston AL, Morton CJ, Ng HL et al (2008) Identification and characterization of a new cognitive enhancer based on inhibition of insulin-regulated aminopeptidase. FASEB J 22:4209–4217
Ascher DB, Polekhina G, Parker MW (2012) Crystallization and preliminary X-ray diffraction analysis of human endoplasmic reticulum aminopeptidase 2. Acta Crystallogr Sect F: Struct Biol Cryst Commun 68:468–471
Chai SY, Yeatman HR, Parker MW et al (2008) Development of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase. BMC Neurosci 9(Suppl 2):S14
Ye S, Chai SY, Lew RA et al (2008) Identification of modulating residues defining the catalytic cleft of insulin-regulated aminopeptidase. Biochem Cell Biol 86:251–261
Parker LJ, Ascher DB, Gao C et al (2012) Structural approaches to probing metal interaction with proteins. J Inorg Biochem 115:138–147
Parker LJ, Italiano LC, Morton CJ et al (2011) Studies of glutathione transferase P1-1 bound to a platinum(IV)-based anticancer compound reveal the molecular basis of its activation. Chemistry 17:7806–7816
Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9:28–39
Congreve M, Carr R, Murray C et al (2003) A ‘rule of three’ for fragment-based lead discovery? Drug Discov Today 8:876–877
Erlanson DA, Braisted AC, Raphael DR et al (2000) Site-directed ligand discovery. Proc Natl Acad Sci U S A 97:9367–9372
Blundell TL, Jhoti H, Abell C (2002) High-throughput crystallography for lead discovery in drug design. Nat Rev Drug Discov 1:45–54
Congreve M, Murray CW, Blundell TL (2005) Structural biology and drug discovery. Drug Discov Today 10:895–907
Lepre CA, Moore JM, Peng JW (2004) Theory and applications of NMR-based screening in pharmaceutical research. Chem Rev 104:3641–3676
Murray CW, Blundell TL (2010) Structural biology in fragment-based drug design. Curr Opin Struct Biol 20:497–507
Cala O, Guilliere F, Krimm I (2014) NMR-based analysis of protein-ligand interactions. Anal Bioanal Chem 406:943–956
Hartshorn MJ, Murray CW, Cleasby A et al (2005) Fragment-based lead discovery using X-ray crystallography. J Med Chem 48:403–413
Caliandro R, Belviso DB, Aresta BM et al (2013) Protein crystallography and fragment-based drug design. Future Med Chem 5:1121–1140
Navratilova I, Hopkins AL (2010) Fragment screening by surface plasmon resonance. ACS Med Chem Lett 1:44–48
Navratilova I, Hopkins AL (2011) Emerging role of surface plasmon resonance in fragment-based drug discovery. Future Med Chem 3:1809–1820
Shepherd CA, Hopkins AL, Navratilova I (2014) Fragment screening by SPR and advanced application to GPCRs. Biol Prog Biophys Mol 116:113–123
Pantoliano MW, Petrella EC, Kwasnoski JD et al (2001) High-density miniaturized thermal shift assays as a general strategy for drug discovery. J Biomol Screen 6:429–440
Lo MC, Aulabaugh A, Jin G et al (2004) Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery. Anal Biochem 332:153–159
Kranz JK, Schalk-Hihi C (2011) Protein thermal shifts to identify low molecular weight fragments. Methods Enzymol 493:277–298
Leavitt S, Freire E (2001) Direct measurement of protein binding energetics by isothermal titration calorimetry. Curr Opin Struct Biol 11:560–566
Gozalbes R, Carbajo RJ, Pineda-Lucena A (2010) Contributions of computational chemistry and biophysical techniques to fragment-based drug discovery. Curr Med Chem 17:1769–1794
Ladbury JE, Klebe G, Freire E (2010) Adding calorimetric data to decision making in lead discovery: a hot tip. Nat Rev Drug Discov 9:23–27
Valkov E, Sharpe T, Marsh M et al (2012) Targeting protein-protein interactions and fragment-based drug discovery. Top Curr Chem 317:145–179
Whittle PJ, Blundell TL (1994) Protein structure–based drug design. Annu Rev Biophys Biomol Struct 23:349–375
Surade S, Blundell TL (2012) Structural biology and drug discovery of difficult targets: the limits of ligandability. Chem Biol 19:42–50
Blundell TL, Srinivasan N (1996) Symmetry, stability, and dynamics of multidomain and multicomponent protein systems. Proc Natl Acad Sci U S A 93:14243–14248
Pellegrini L, Burke DF, von Delft F et al (2000) Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature 407:1029–1034
Harmer NJ, Ilag LL, Mulloy B et al (2004) Towards a resolution of the stoichiometry of the fibroblast growth factor (FGF)-FGF receptor-heparin complex. J Mol Biol 339:821–834
Robinson CJ, Harmer NJ, Goodger SJ et al (2005) Cooperative dimerization of fibroblast growth factor 1 (FGF1) upon a single heparin saccharide may drive the formation of 2:2:1 FGF1.FGFR2c.heparin ternary complexes. J Biol Chem 280:42274–42282
Brown A, Robinson CJ, Gallagher JT et al (2013) Cooperative heparin-mediated oligomerization of fibroblast growth factor-1 (FGF1) precedes recruitment of FGFR2 to ternary complexes. Biophys J 104:1720–1730
Chirgadze DY, Hepple JP, Zhou H et al (1999) Crystal structure of the NK1 fragment of HGF/SF suggests a novel mode for growth factor dimerization and receptor binding. Nat Struct Biol 6:72–79
Gherardi E, Youles ME, Miguel RN et al (2003) Functional map and domain structure of MET, the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor. Proc Natl Acad Sci U S A 100:12039–12044
Gherardi E, Sandin S, Petoukhov MV et al (2006) Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci U S A 103:4046–4051
Higueruelo AP, Jubb H, Blundell TL (2013) Protein-protein interactions as druggable targets: recent technological advances. Curr Opin Pharmacol 13:791–796
Herbert C, Schieborr U, Saxena K et al (2013) Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling. Cancer Cell 23:489–501
Bolanos-Garcia VM, Wu Q, Ochi T et al (2012) Spatial and temporal organization of multi-protein assemblies: achieving sensitive control in information-rich cell-regulatory systems. Philos Transact A Math Phys Eng Sci 370:3023–3039
Sibanda BL, Critchlow SE, Begun J et al (2001) Crystal structure of an Xrcc4-DNA ligase IV complex. Nat Struct Biol 8:1015–1019
Sibanda BL, Chirgadze DY, Blundell TL (2010) Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats. Nature 463:118–121
Singleton BK, Torres-Arzayus MI, Rottinghaus ST et al (1999) The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit. Mol Cell Biol 19:3267–3277
Gell D, Jackson SP (1999) Mapping of protein-protein interactions within the DNA-dependent protein kinase complex. Nucleic Acids Res 27:3494–3502
Nick McElhinny SA, Snowden CM, McCarville J et al (2000) Ku recruits the XRCC4-ligase IV complex to DNA ends. Mol Cell Biol 20:2996–3003
Yano K, Morotomi-Yano K, Wang SY et al (2008) Ku recruits XLF to DNA double-strand breaks. EMBO Rep 9:91–96
Sasaki K, Dockerill S, Adamiak DA et al (1975) X-ray analysis of glucagon and its relationship to receptor binding. Nature 257:751–757
Pellegrini L, Yu DS, Lo T et al (2002) Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature 420:287–293
Dyson HJ, Wright PE (2002) Coupling of folding and binding for unstructured proteins. Curr Opin Struct Biol 12:54–60
Hernandez H, Robinson CV (2007) Determining the stoichiometry and interactions of macromolecular assemblies from mass spectrometry. Nat Protoc 2:715–726
Sharon M, Robinson CV (2007) The role of mass spectrometry in structure elucidation of dynamic protein complexes. Annu Rev Biochem 76:167–193
Ascher DB, Cromer BA, Morton CJ et al (2011) Regulation of insulin-regulated membrane aminopeptidase activity by its C-terminal domain. Biochemistry 50:2611–2622
Ascher DB, Wielens J, Nero TL et al (2014) Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA. Sci Rep 4:4765
Polekhina G, Ascher DB, Kok SF et al (2013) Structure of the N-terminal domain of human thioredoxin-interacting protein. Acta Crystallogr D Biol Crystallogr 69:333–344
Rambo RP, Tainer JA (2013) Accurate assessment of mass, models and resolution by small-angle scattering. Nature 496:477–481
Koch MH, Vachette P, Svergun DI (2003) Small-angle scattering: a view on the properties, structures and structural changes of biological macromolecules in solution. Q Rev Biophys 36:147–227
Putnam CD, Hammel M, Hura GL et al (2007) X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution. Q Rev Biophys 40:191–285
Hammel M, Yu Y, Fang S et al (2010) XLF regulates filament architecture of the XRCC4.ligase IV complex. Structure 18:1431–1442
Wong W, Bai XC, Brown A et al (2014) Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine. Elife 3:e03080
Davis AJ, Chen BP, Chen DJ (2014) DNA-PK: a dynamic enzyme in a versatile DSB repair pathway. DNA Repair (Amst) 17:21–29
Yang H, Rudge DG, Koos JD et al (2013) mTOR kinase structure, mechanism and regulation. Nature 497:217–223
Boskovic J, Rivera-Calzada A, Maman JD et al (2003) Visualization of DNA-induced conformational changes in the DNA repair kinase DNA-PKcs. EMBO J 22:5875–5882
Chiu CY, Cary RB, Chen DJ et al (1998) Cryo-EM imaging of the catalytic subunit of the DNA-dependent protein kinase. J Mol Biol 284:1075–1081
Leuther KK, Hammarsten O, Kornberg RD et al (1999) Structure of DNA-dependent protein kinase: implications for its regulation by DNA. EMBO J 18:1114–1123
Williams DR, Lee KJ, Shi J et al (2008) Cryo-EM structure of the DNA-dependent protein kinase catalytic subunit at subnanometer resolution reveals alpha helices and insight into DNA binding. Structure 16:468–477
Hammel M, Yu Y, Mahaney BL et al (2010) Ku and DNA-dependent protein kinase dynamic conformations and assembly regulate DNA binding and the initial non-homologous end joining complex. J Biol Chem 285:1414–1423
Morris EP, Rivera-Calzada A, da Fonseca PC et al (2011) Evidence for a remodelling of DNA-PK upon autophosphorylation from electron microscopy studies. Nucleic Acids Res 39:5757–5767
Spagnolo L, Rivera-Calzada A, Pearl LH et al (2006) Three-dimensional structure of the human DNA-PKcs/Ku70/Ku80 complex assembled on DNA and its implications for DNA DSB repair. Mol Cell 22:511–519
Cary RB, Peterson SR, Wang J et al (1997) DNA looping by Ku and the DNA-dependent protein kinase. Proc Natl Acad Sci U S A 94:4267–4272
Yaneva M, Kowalewski T, Lieber MR (1997) Interaction of DNA-dependent protein kinase with DNA and with Ku: biochemical and atomic-force microscopy studies. EMBO J 16:5098–5112
Ochi T, Wu Q, Blundell TL (2014) The spatial organization of non-homologous end joining: from bridging to end joining. DNA Repair (Amst) 17:98–109
Andres SN, Vergnes A, Ristic D et al (2012) A human XRCC4-XLF complex bridges DNA. Nucleic Acids Res 40:1868–1878
Hammel M, Rey M, Yu Y et al (2011) XRCC4 protein interactions with XRCC4-like factor (XLF) create an extended grooved scaffold for DNA ligation and double strand break repair. J Biol Chem 286:32638–32650
Ropars V, Drevet P, Legrand P et al (2011) Structural characterization of filaments formed by human Xrcc4-Cernunnos/XLF complex involved in nonhomologous DNA end-joining. Proc Natl Acad Sci U S A 108:12663–12668
Wu Q, Ochi T, Matak-Vinkovic D et al (2011) Non-homologous end-joining partners in a helical dance: structural studies of XLF-XRCC4 interactions. Biochem Soc Trans 39:1387–1392, suppl 2 p following 1392
Ochi T, Wu Q, Chirgadze DY et al (2012) Structural insights into the role of domain flexibility in human DNA ligase IV. Structure 20:1212–1222
Williams GJ, Hammel M, Radhakrishnan SK et al (2014) Structural insights into NHEJ: building up an integrated picture of the dynamic DSB repair super complex, one component and interaction at a time. DNA Repair (Amst) 17:110–120
Critchlow SE, Bowater RP, Jackson SP (1997) Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV. Curr Biol 7:588–598
Grawunder U, Zimmer D, Lieber MR (1998) DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains. Curr Biol 8:873–876
Recuero-Checa MA, Dore AS, Arias-Palomo E et al (2009) Electron microscopy of Xrcc4 and the DNA ligase IV-Xrcc4 DNA repair complex. DNA Repair (Amst) 8:1380–1389
Ochi T, Gu X, Blundell TL (2013) Structure of the catalytic region of DNA ligase IV in complex with an Artemis fragment sheds light on double-strand break repair. Structure 21:672–679
Berman HM, Westbrook J, Feng Z et al (2000) The protein data bank. Nucleic Acids Res 28:235–242
Dou Y, Baisnee PF, Pollastri G et al (2004) ICBS: a database of interactions between protein chains mediated by beta-sheet formation. Bioinformatics 20:2767–2777
Lo A, Cheng CW, Chiu YY et al (2011) TMPad: an integrated structural database for helix-packing folds in transmembrane proteins. Nucleic Acids Res 39:D347–D355
Mosca R, Ceol A, Stein A et al (2014) 3did: a catalog of domain-based interactions of known three-dimensional structure. Nucleic Acids Res 42:D374–D379
Huang Z, Zhu L, Cao Y et al (2011) ASD: a comprehensive database of allosteric proteins and modulators. Nucleic Acids Res 39:D663–D669
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–D516
Bickerton GR, Higueruelo AP, Blundell TL (2011) Comprehensive, atomic-level characterization of structurally characterized protein-protein interactions: the PICCOLO database. BMC Bioinf 12:313
Lee S, Blundell TL (2009) BIPA: a database for protein-nucleic acid interaction in 3D structures. Bioinformatics 25:1559–1560
Schreyer A, Blundell T (2009) CREDO: a protein-ligand interaction database for drug discovery. Chem Biol Drug Des 73:157–167
Schreyer AM, Blundell TL (2013) CREDO: a structural interactomics database for drug discovery. Database (Oxford) 2013:bat049
Hamosh A, Scott AF, Amberger JS et al (2005) Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res 33:D514–D517
Forbes SA, Bhamra G, Bamford S et al (2008) The catalogue of somatic mutations in cancer (COSMIC). Curr Protoc Hum Genet, Chapter 10:Unit 10 11
Apweiler R, Bairoch A, Wu CH et al (2004) UniProt: the Universal Protein knowledgebase. Nucleic Acids Res 32:D115–D119
Hubbard T, Barker D, Birney E et al (2002) The Ensembl genome database project. Nucleic Acids Res 30:38–41
Gaulton A, Bellis LJ, Bento AP et al (2011) ChEMBL: a large-scale bioactivity database for drug discovery. Nucleic Acids Res 40:D1100–D1107
Lewell XQ, Judd DB, Watson SP et al (1998) RECAP-Retrosynthetic combinatorial analysis procedure: a powerful new technique for identifying privileged molecular fragments with useful applications in combinatorial chemistry. J Chem Inf Comput Sci 38:511–522
Deng Z, Chuaqui C, Singh J (2004) Structural interaction fingerprint (SIFt): a novel method for analyzing three-dimensional protein-ligand binding interactions. J Med Chem 47:337–344
Blundell TL, Sibanda BL, Montalvao RW et al (2006) Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Philos Trans R Soc Lond B Biol Sci 361:413–423
Nair SK, Burley SK (2003) X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell 112:193–205
Fletcher S, Hamilton AD (2006) Targeting protein-protein interactions by rational design: mimicry of protein surfaces. J R Soc Interface 3:215–233
Jones S, Thornton JM (1996) Principles of protein-protein interactions. Proc Natl Acad Sci U S A 93:13–20
Arkin MR, Tang Y, Wells JA (2014) Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem Biol 21:1102–1114
Cooper A (1999) Thermodynamic analysis of biomolecular interactions. Curr Opin Chem Biol 3:557–563
Breiten B, Lockett MR, Sherman W et al (2013) Water networks contribute to enthalpy/entropy compensation in protein-ligand binding. J Am Chem Soc 135:15579–15584
Fuller JC, Burgoyne NJ, Jackson RM (2009) Predicting druggable binding sites at the protein-protein interface. Drug Discov Today 14:155–161
Li X, Keskin O, Ma B et al (2004) Protein-protein interactions: hot spots and structurally conserved residues often locate in complemented pockets that pre-organized in the unbound states: implications for docking. J Mol Biol 344:781–795
Clackson T, Wells JA (1995) A hot spot of binding energy in a hormone-receptor interface. Science 267:383–386
Bogan AA, Thorn KS (1998) Anatomy of hot spots in protein interfaces. J Mol Biol 280:1–9
Rajamani D, Thiel S, Vajda S et al (2004) Anchor residues in protein-protein interactions. Proc Natl Acad Sci U S A 101:11287–11292
Ben-Shimon A, Eisenstein M (2010) Computational mapping of anchoring spots on protein surfaces. J Mol Biol 402:259–277
Meireles LM, Domling AS, Camacho CJ (2010) ANCHOR: a web server and database for analysis of protein-protein interaction binding pockets for drug discovery. Nucleic Acids Res 38:W407–W411
Koes DR, Camacho CJ (2012) PocketQuery: protein-protein interaction inhibitor starting points from protein-protein interaction structure. Nucleic Acids Res 40:W387–W392
London N, Movshovitz-Attias D, Schueler-Furman O (2010) The structural basis of peptide-protein binding strategies. Structure 18:188–199
London N, Raveh B, Movshovitz-Attias D et al (2010) Can self-inhibitory peptides be derived from the interfaces of globular protein-protein interactions? Proteins 78:3140–3149
London N, Raveh B, Schueler-Furman O (2013) Druggable protein-protein interactions–from hot spots to hot segments. Curr Opin Chem Biol 17:952–959
Pommier Y, Marchand C (2012) Interfacial inhibitors: targeting macromolecular complexes. Nat Rev Drug Discov 11:25–36
Gao M, Skolnick J (2012) The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation. Proc Natl Acad Sci U S A 109:3784–3789
Topham CM, Srinivasan N, Blundell TL (1997) Prediction of the stability of protein mutants based on structural environment-dependent amino acid substitution and propensity tables. Protein Eng 10:7–21
Worth CL, Preissner R, Blundell TL (2011) SDM–a server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Res 39:W215–W222
Overington J, Donnelly D, Johnson MS et al (1992) Environment-specific amino acid substitution tables: tertiary templates and prediction of protein folds. Protein Sci 1:216–226
Kucukkal TG, Yang Y, Chapman SC et al (2014) Computational and experimental approaches to reveal the effects of single nucleotide polymorphisms with respect to disease diagnostics. Int J Mol Sci 15:9670–9717
Pires DE, Ascher DB, Blundell TL (2014) mCSM: predicting the effects of mutations in proteins using graph-based signatures. Bioinformatics 30:335–342
da Silveira CH, Pires DE, Minardi RC et al (2009) Protein cutoff scanning: a comparative analysis of cutoff dependent and cutoff free methods for prospecting contacts in proteins. Proteins 74:727–743
Pires DE, de Melo-Minardi RC, Ados Santos M et al (2011) Cutoff Scanning Matrix (CSM): structural classification and function prediction by protein inter-residue distance patterns. BMC Genomics 12(Suppl 4):S12
Pires DE, de Melo-Minardi RC, da Silveira CH et al (2013) aCSM: noise-free graph-based signatures to large-scale receptor-based ligand prediction. Bioinformatics 29:855–861
Guerois R, Nielsen JE, Serrano L (2002) Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J Mol Biol 320:369–387
Kortemme T, Baker D (2002) A simple physical model for binding energy hot spots in protein-protein complexes. Proc Natl Acad Sci U S A 99:14116–14121
Kortemme T, Kim DE, Baker D (2004) Computational alanine scanning of protein-protein interfaces. Sci STKE 2004:pl2
Huo S, Massova I, Kollman PA (2002) Computational alanine scanning of the 1:1 human growth hormone-receptor complex. J Comput Chem 23:15–27
Gouda H, Kuntz ID, Case DA et al (2003) Free energy calculations for theophylline binding to an RNA aptamer: comparison of MM-PBSA and thermodynamic integration methods. Biopolymers 68:16–34
Kollman PA, Massova I, Reyes C et al (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889–897
Kollman P (1993) Free energy calculations: applications to chemical and biochemical phenomena. Chem Rev 93:2395–2417
Kong X, Brooks C (1996) Lambda-dynamics: a new approach to free energy calculations. J Chem Phys 105:2414–2423
Moreira I, Fernandes P, Ramos M (2007) Unravelling Hot Spots: a comprehensive computational mutagenesis study. Theor Chem Accounts 117:99–113
Moreira IS, Fernandes PA, Ramos MJ (2005) Accuracy of the numerical solution of the Poisson–Boltzmann equation. J Mol Struct THEOCHEM 729:11–18
Massova I, Kollman PA (1999) Computational alanine scanning to probe protein–protein interactions: a novel approach to evaluate binding free energies. J Am Chem Soc 121: 8133–8143
Moal IH, Fernandez-Recio J (2012) SKEMPI: a structural kinetic and energetic database of mutant protein interactions and its use in empirical models. Bioinformatics 28:2600–2607
Dehouck Y, Kwasigroch JM, Rooman M et al (2013) BeAtMuSiC: prediction of changes in protein-protein binding affinity on mutations. Nucleic Acids Res 41:W333–W339
Dourado DF, Flores SC (2014) A multiscale approach to predicting affinity changes in protein-protein interfaces. Proteins 82:2681–2690
Li M, Petukh M, Alexov E et al (2014) Predicting the impact of missense mutations on protein-protein binding affinity. J Chem Theory Comput 10:1770–1780
Moal IH, Fernandez-Recio J (2013) Intermolecular contact potentials for protein–protein interactions extracted from binding free energy changes upon mutation. J Chem Theory Comput 9:3715–3727
Gossage L, Pires DE, Olivera-Nappa A et al (2014) An integrated computational approach can classify VHL missense mutations according to risk of clear cell renal carcinoma. Hum Mol Genet 23:5976–5988
Pires DE, Ascher DB, Blundell TL (2014) DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res 42:W314–W319
Fletcher S, Hamilton AD (2005) Protein surface recognition and proteomimetics: mimics of protein surface structure and function. Curr Opin Chem Biol 9:632–638
Wilson AJ (2009) Inhibition of protein-protein interactions using designed molecules. Chem Soc Rev 38:3289–3300
Buerger C, Groner B (2003) Bifunctional recombinant proteins in cancer therapy: cell penetrating peptide aptamers as inhibitors of growth factor signaling. J Cancer Res Clin Oncol 129:669–675
Seidah NG (2013) Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies. Curr Pharm Des 19:3161–3172
Traczewski P, Rudnicka L (2011) Treatment of systemic lupus erythematosus with epratuzumab. Br J Clin Pharmacol 71:175–182
Nord K, Gunneriusson E, Ringdahl J et al (1997) Binding proteins selected from combinatorial libraries of an alpha-helical bacterial receptor domain. Nat Biotechnol 15:772–777
Kaminskas LM, Ascher DB, McLeod VM et al (2013) PEGylation of interferon alpha2 improves lymphatic exposure after subcutaneous and intravenous administration and improves antitumour efficacy against lymphatic breast cancer metastases. J Control Release 168:200–208
Basse MJ, Betzi S, Bourgeas R et al (2013) 2P2Idb: a structural database dedicated to orthosteric modulation of protein-protein interactions. Nucleic Acids Res 41:D824–D827
Higueruelo AP, Jubb H, Blundell TL (2013) TIMBAL v2: update of a database holding small molecules modulating protein-protein interactions. Database (Oxford) 2013:bat039
Higueruelo AP, Schreyer A, Bickerton GRJ et al (2009) Atomic interactions and profile of small molecules disrupting protein-protein interfaces: the TIMBAL database. Chem Biol Drug Des 74:457–467
Hann MM (2011) Molecular obesity, potency and other addictions in drug discovery. MedChemComm 2:349–355
Higueruelo AP, Schreyer A, Bickerton GRJ et al (2012) What can we learn from the evolution of protein-ligand interactions to aid the design of new therapeutics? PLoS One 7:e51742
Arkin MR, Randal M, DeLano WL et al (2003) Binding of small molecules to an adaptive protein-protein interface. Proc Natl Acad Sci U S A 100:1603–1608
Sauve K, Nachman M, Spence C et al (1991) Localization in human interleukin 2 of the binding site to the alpha chain (p55) of the interleukin 2 receptor. Proc Natl Acad Sci U S A 88:4636–4640
Zurawski SM, Vega F Jr, Doyle EL et al (1993) Definition and spatial location of mouse interleukin-2 residues that interact with its heterotrimeric receptor. EMBO J 12:5113–5119
Scott DE, Ehebauer MT, Pukala T et al (2013) Using a fragment-based approach to target protein-protein interactions. Chembiochem 14:332–342
Wyatt PG, Woodhead AJ, Berdini V et al (2008) Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design. J Med Chem 51:4986–4999
Howard S, Berdini V, Boulstridge JA et al (2009) Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem 52:379–388
Frederickson M, Callaghan O, Chessari G et al (2008) Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator. J Med Chem 51:183–186
Antonysamy SS, Aubol B, Blaney J et al (2008) Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors. Bioorg Med Chem Lett 18:2990–29995
Antonysamy S, Hirst G, Park F et al (2009) Fragment-based discovery of JAK-2 inhibitors. Bioorg Med Chem Lett 19:279–282
Edfeldt FNB, Folmer RHA, Breeze AL (2011) Fragment screening to predict druggability (ligandability) and lead discovery success. Drug Discov Today 16:284–287
Winter A, Higueruelo P et al (2012) Biophysical and computational fragment-based approaches to targeting protein-protein interactions: applications in structure-guided drug discovery. Q Rev Biophys 45:383–426
Jubb H, Higueruelo A, Winter A et al (2012) Structural biology and drug discovery for protein–protein interactions. Trends Pharmacol Sci 33:241–248
Keserü GM, Makara GM (2009) The influence of lead discovery strategies on the properties of drug candidates. Nat Rev Drug Discov 8:203–212
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Ascher, D.B., Jubb, H.C., Pires, D.E.V., Ochi, T., Higueruelo, A., Blundell, T.L. (2015). Protein-Protein Interactions: Structures and Druggability. In: Scapin, G., Patel, D., Arnold, E. (eds) Multifaceted Roles of Crystallography in Modern Drug Discovery. NATO Science for Peace and Security Series A: Chemistry and Biology. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9719-1_12
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DOI: https://doi.org/10.1007/978-94-017-9719-1_12
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