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Biophysical and computational fragment-based approaches to targeting protein–protein interactions: applications in structure-guided drug discovery

  • Anja Winter (a1), Alicia P. Higueruelo (a1), May Marsh (a1), Anna Sigurdardottir (a1), Will R Pitt (a1) (a2) and Tom L. Blundell (a1)
  • DOI: http://dx.doi.org/10.1017/S0033583512000108
  • Published online: 13 September 2012
Abstract
Abstract

Drug discovery has classically targeted the active sites of enzymes or ligand-binding sites of receptors and ion channels. In an attempt to improve selectivity of drug candidates, modulation of protein–protein interfaces (PPIs) of multiprotein complexes that mediate conformation or colocation of components of cell-regulatory pathways has become a focus of interest. However, PPIs in multiprotein systems continue to pose significant challenges, as they are generally large, flat and poor in distinguishing features, making the design of small molecule antagonists a difficult task. Nevertheless, encouragement has come from the recognition that a few amino acids – so-called hotspots – may contribute the majority of interaction-free energy. The challenges posed by protein–protein interactions have led to a wellspring of creative approaches, including proteomimetics, stapled α-helical peptides and a plethora of antibody inspired molecular designs. Here, we review a more generic approach: fragment-based drug discovery. Fragments allow novel areas of chemical space to be explored more efficiently, but the initial hits have low affinity. This means that they will not normally disrupt PPIs, unless they are tethered, an approach that has been pioneered by Wells and co-workers. An alternative fragment-based approach is to stabilise the uncomplexed components of the multiprotein system in solution and employ conventional fragment-based screening. Here, we describe the current knowledge of the structures and properties of protein–protein interactions and the small molecules that can modulate them. We then describe the use of sensitive biophysical methods – nuclear magnetic resonance, X-ray crystallography, surface plasmon resonance, differential scanning fluorimetry or isothermal calorimetry – to screen and validate fragment binding. Fragment hits can subsequently be evolved into larger molecules with higher affinity and potency. These may provide new leads for drug candidates that target protein–protein interactions and have therapeutic value.

Copyright
Corresponding author
*Author for correspondence: Tom Blundell, The University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. Tel:+44(0)1223 333628; Email: tlb20@cam.ac.uk
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This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

N. Abdel-Rahman , A. Martinez-Arias & T.L. Blundell (2011). Probing the druggability of protein–protein interactions: targeting the Notch1 receptor ankyrin domain using a fragment-based approach. Biochemical Society Transactions 39, 13271333.

S. Barelier , J. Pon , O. Marcillat , J.M. Lancelin & I. Krimm (2010). Fragment-based deconstruction of Bcl-XL inhibitors. Journal of Medical Chemistry 53, 25772588.

F. Bernal , M. Wade , M. Godes , T.N. Davis , D.G. Whitehead , A.L. Kung , G.M. Wahl & L.D. Walensky (2010). A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell 18, 411422.

J.L. Best , C.A. Amezcua , B. Mayr , L. Flechner , C.M. Murawsky , B. Emerson , T. Zor , K.H. Gardner & M. Montminy (2004). Identification of small-molecule antagonists that inhibit an activator:coactivator interaction. Proceedings of the National Academy of Sciences of the United States of America 101, 1762217627.

G.R. Bickerton , A.P. Higueruelo & T.L. Blundell (2011). Comprehensive, atomic-level characterization of structurally characterized protein–protein interactions: the PICCOLO database. BMC Bioinformatics 12, 313.

T. Blundell (1979). Conformation and molecular biology of polypeptide hormones II. Glucagon. Trends in Biochemical Sciences 4, 8083.

T. Blundell & S. Wood (1982). The conformation, flexibility and dynamics of polypeptide hormones. Annual Review of Biochemistry 51, 123154.

T.L. Blundell , D.F. Burke , D. Chirgadze , V. Dhanaraj , M. Hyvonen , C.A. Innis , E. Parisini , L. Pellegrini , M. Sayed & B.L. Sibanda (2000). Protein–protein interactions in receptor activation and intracellular signalling. Biological Chemistry 381, 955959.

T.L. Blundell , H. Jhoti & C. Abell (2002). High-throughput crystallography for lead discovery in drug design. Nature Reviews Drug Discovery 1, 4554.

T.L. Blundell , B.L. Sibanda , R.W. Montalvao , S. Brewerton , V. Chelliah , C.L. Worth , N.J. Harmer , O. Davies & D. Burke (2006). Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 361, 413423.

D.D. Boehr , R. Nussinov & P.E. Wright (2009). The role of dynamic conformational ensembles in biomolecular recognition. Nature Chemical Biology 5, 789796.

A.A. Bogan & K.S. Thorn (1998). Anatomy of hot spots in protein interfaces. Journal of Molecular Biology 280, 19.

A.J. Bordner (2009). Predicting protein–protein binding sites in membrane proteins. BMC Bioinformatics 10, 312.

R. Bourgeas , M.J. Basse , X. Morelli & P. Roche (2010). Atomic analysis of protein–protein interfaces with known inhibitors: the 2P2I database. PLoS ONE 5, e9598.

S. Boyden (1962). The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. Journal of Experimental Medicine 115, 453466.

J.F. Brandts & L.N. Lin (1990). Study of strong to ultratight protein interactions using differential scanning calorimetry. Biochemistry 29, 69276940.

W. Braun , G. Wider , K.H. Lee & K. Wuthrich (1983). Conformation of glucagon in a lipid–water interphase by 1H nuclear magnetic resonance. Journal of Molecular Biology 169, 921948.

M. Bruncko , T.K. Oost , B.A. Belli , H. Ding , M.K. Joseph , A. Kunzer , D. Martineau , W.J. Mcclellan , M. Mitten , S.C. Ng , P.M. Nimmer , T. Oltersdorf , C.M. Park , A.M. Petros , A.R. Shoemaker , X. Song , X. Wang , M.D. Wendt , H. Zhang , S.W. Fesik , S.H. Rosenberg & S.W. Elmore (2007). Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-XL. Journal of Medical Chemistry 50, 641662.

C. Buerger & B. Groner (2003). Bifunctional recombinant proteins in cancer therapy: cell penetrating peptide aptamers as inhibitors of growth factor signaling. Journal of Cancer Research and Clinical Oncology 129, 669675.

D. Cardinale , O.M. Salo-Ahen , S. Ferrari , G. Ponterini , G. Cruciani , E. Carosati , A.M. Tochowicz , S. Mangani , R.C. Wade & M.P. Costi (2010). Homodimeric enzymes as drug targets. Current Medicinal Chemistry 17, 826846.

R. Carr & H. Jhoti (2002). Structure-based screening of low-affinity compounds. Drug Discovery Today 7, 522527.

R.A. Carr , M. Congreve , C.W. Murray & D.C. Rees (2005). Fragment-based lead discovery: leads by design. Drug Discovery Today 10, 987992.

M.S. Celej , G.G. Montich & G.D. Fidelio (2003). Protein stability induced by ligand binding correlates with changes in protein flexibility. Protein Science: A Publication of the Protein Society 12, 14961506.

P. Chakrabarti & R. Bhattacharyya (2007). Geometry of nonbonded interactions involving planar groups in proteins. Progress in Biophysics and Molecular Biology 95, 83137.

A. Chatr-Aryamontri , A. Ceol , L.M. Palazzi , G. Nardelli , M.V. Schneider , L. Castagnoli & G. Cesareni (2007). MINT: the Molecular INTeraction database. Nucleic Acids Research 35, D572D574.

J. Chen , X.F. Zheng , E.J. Brown & S.L. Schreiber (1995). Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proceedings of the National Academy of Sciences of the United States of America 92, 49474951.

J. Choi , J. Chen , S.L. Schreiber & J. Clardy (1996). Structure of the FKBP12–rapamycin complex interacting with the binding domain of human FRAP. Science 273, 239242.

Y.S. Choi , J. Hur , H.K. Lee & S. Jeong (2009). The RNA aptamer disrupts protein–protein interaction between beta-catenin and nuclear factor-kappaB p50 and regulates the expression of C-reactive protein. FEBS Letters 583, 14151421.

S. Chung , J.B. Parker , M. Bianchet , L.M. Amzel & J.T. Stivers (2009). Impact of linker strain and flexibility in the design of a fragment-based inhibitor. Nature Chemical Biology 5, 407413.

P. Cimmperman , L. Baranauskiene , S. Jachimoviciute , J. Jachno , J. Torresan , V. Michailoviene , J. Matuliene , J. Sereikaite , V. Bumelis & D. Matulis (2008). A quantitative model of thermal stabilization and destabilization of proteins by ligands. Biophysics Journal 95, 32223231.

A. Ciulli , G. Williams , A.G. Smith , T.L. Blundell & C. Abell (2006). Probing hot spots at protein-ligand binding sites: a fragment-based approach using biophysical methods. Journal of Medical Chemistry 49, 49925000.

T. Clackson & J.A. Wells (1995). A hot spot of binding energy in a hormone–receptor interface. Science 267, 383386.

D.C. Cole , A.M. Olland , J. Jacob , J. Brooks , M.G. Bursavich , R. Czerwinski , C. Declercq , M. Johnson , D. Joseph-Mccarthy , J.W. Ellingboe , L. Lin , P. Nowak , E. Presman , J. Strand , A. Tam , C.M. Williams , S. Yao , D.H. Tsao & L.J. Fitz (2010). Identification and characterization of acidic mammalian chitinase inhibitors. Journal of Medical Chemistry 53, 61226128.

M. Congreve , R. Carr , C. Murray & H. Jhoti (2003). A ‘rule of three’ for fragment-based lead discovery? Drug Discovery Today 8, 876877.

M. Congreve , G. Chessari , D. Tisi & A.J. Woodhead (2008). Recent developments in fragment-based drug discovery. Journal of Medical Chemistry 51, 36613680.

M. Congreve , C.W. Murray & T.L. Blundell (2005). Structural biology and drug discovery. Drug Discovery Today 10, 895907.

M. Congreve , R.L. Rich , D.G. Myszka , F. Figaroa , G. Siegal & F.H. Marshall (2011). Fragment screening of stabilized G-protein-coupled receptors using biophysical methods. Methods in Enzymology 493, 115136.

A. D'arcy , F. Villard & M. Marsh (2007). An automated microseed matrix-screening method for protein crystallization. Acta Crystallographica, Section D, Biological Crystallography 63(Pt 4), 550554.

C. Dalvit , P. Pevarello , M. Tato , M. Veronesi , A. Vulpetti & M. Sundstrom (2000). Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water. Journal of Biomolecular NMR 18, 6568.

T.G. Davies , R.L.M. van Montfort , G. Williams & H. Jhoti (2006). Pyramid: an integrated platform for fragment-based drug discovery. In Fragment-based Approaches in Drug Discovery, pp. 193214. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA.

F.P. Davis & A. Sali (2005). PIBASE: a comprehensive database of structurally defined protein interfaces. Bioinformatics 21, 19011907.

F.P. Davis & A. Sali (2010). The overlap of small molecule and protein binding sites within families of protein structures. PLoS Computational Biology 6, e1000668.

P.M. Dean , S. Firth-Clark , W. Harris , S.B. Kirton & N.P. Todorov (2006). SkelGen: a general tool for structure-based de novo ligand design. Expert Opinion on Drug Discovery 1, 179189.

A. Del Sol & P. O'MEARA (2005). Small-world network approach to identify key residues in protein–protein interaction. Proteins 58, 672682.

F. Dey & A. Caflisch (2008). Fragment-based de novo ligand design by multiobjective evolutionary optimization. Journal of Chemical Information Modeling 48, 679690.

P. Dorr , M. Westby , S. Dobbs , P. Griffin , B. Irvine , M. Macartney , J. Mori , G. Rickett , C. Smith-Burchnell , C. Napier , R. Webster , D. Armour , D. Price , B. Stammen , A. Wood & M. Perros (2005). Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrobial Agents and Chemotherapy 49, 47214732.

Y. Dou , P.F. Baisnee , G. Pollastri , Y. Pecout , J. Nowick & P. Baldi (2004). ICBS: a database of interactions between protein chains mediated by beta-sheet formation. Bioinformatics 20, 27672777.

D. Douguet (2010). e-LEA3D: a computational-aided drug design web server. Nucleic Acids Research 38(Web Server issue), W615W621.

D. Douguet , H. Munier-Lehmann , G. Labesse & S. Pochet (2005). LEA3D: a computer-aided ligand design for structure-based drug design. Journal of Medical Chemistry 48, 24572468.

J. Durrant , R. Amaro & J. Mccammon (2009). AutoGrow: a novel algorithm for protein inhibitor design. Chemical Biology & Drug Design 73, 168178.

H.J. Dyson & P.E. Wright (2002). Coupling of folding and binding for unstructured proteins. Current Opinion in Structural Biology 12, 5460.

F.N. Edfeldt , R.H. Folmer & A.L. Breeze (2011). Fragment screening to predict druggability (ligandability) and lead discovery success. Drug Discovery Today 16, 284287.

E. Edink , P. Rucktooa , K. Retra , A. Akdemir , T. Nahar , O. Zuiderveld , R. Van Elk , E. Janssen , P. Van Nierop , J. Van Muijlwijk-Koezen , A.B. Smit , T.K. Sixma , R. Leurs & I.J. De Esch (2011). Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis. Journal of the American Chemical Society 133, 53635371.

M. Elinder , M. Geitmann , T. Gossas , P. Kallblad , J. Winquist , H. Nordstrom , M. Hamalainen & U.H. Danielson (2011). Experimental validation of a fragment library for lead discovery using SPR biosensor technology. Journal of Biomolecular Screening: The Official Journal of the Society for Biomolecular Screening 16, 1525.

D.A. Erlanson , A.C. Braisted , D.R. Raphael , M. Randal , R.M. Stroud , E.M. Gordon & J.A. Wells (2000). Site-directed ligand discovery. Proceedings of the National Academy of Sciences of the United States of America 97, 93679372.

D.A. Erlanson , J.W. Lam , C. Wiesmann , T.N. Luong , R.L. Simmons , W.L. Delano , I.C. Choong , M.T. Burdett , W.M. Flanagan , D. Lee , E.M. Gordon & T. O'Brien (2003). In situ assembly of enzyme inhibitors using extended tethering. Nature Biotechnology 21 308314.

G.G. Ferenczy & G.M. Keserü (2010). Enthalpic efficiency of ligand binding. Journal of Chemical Information Model 50, 15361541.

D.M. Ferraris , E. Gherardi , Y. Di , D.W. Heinz & H.H. Niemann (2009). Ligand-mediated dimerization of the Met receptor tyrosine kinase by the bacterial invasion protein InlB. Journal of Molecular Biology 395, 522532.

T.B. Fischer , K.V. Arunachalam , D. Bailey , V. Mangual , S. Bakhru , R. Russo , D. Huang , M. Paczkowski , V. Lalchandani , C. Ramachandra , B. Ellison , S. Galer , J. Shapley , E. Fuentes & J. Tsai (2003). The binding interface database (BID): a compilation of amino acid hot spots in protein interfaces. Bioinformatics 19, 14531454.

P.A. Fitzpatrick , A.C. Steinmetz , D. Ringe & A.M. Klibanov (1993). Enzyme crystal structure in a neat organic solvent. Proceedings of the National Academy of Sciences of the United States of America 90, 86538657.

S. Fletcher & A.D. Hamilton (2005). Protein surface recognition and proteomimetics: mimics of protein surface structure and function. Current Opinion in Chemical Biology 9, 632638.

J.C. Fuller , N.J. Burgoyne & R.M. Jackson (2009). Predicting druggable binding sites at the protein–protein interface. Drug Discovery Today 14, 155161.

J. Gabadinho , D. Hall , G. Leonard , E. Gordon , S. Monaco & X. Thibault (2008). Remote access experiments at the macromolecular crystallography beamlines of the ESRF. Synchrotron Radiation News 21, 2429.

Y. Gao , D. Douguet , A. Tovchigrechko & I.A. Vakser (2007). DOCKGROUND system of databases for protein recognition studies: unbound structures for docking. Proteins 69, 845851.

D.S. Garrett , Y.J. Seok , A. Peterkofsky , G.M. Clore & A.M. Gronenborn (1997). Identification by NMR of the binding surface for the histidine-containing phosphocarrier protein HPr on the N-terminal domain of enzyme I of the Escherichia coli phosphotransferase system. Biochemistry 36, 43934398.

S. Geschwindner , L.L. Olsson , J.S. Albert , J. Deinum , P.D. Edwards , T. De Beer & R.H. Folmer (2007). Discovery of a novel warhead against beta-secretase through fragment-based lead generation. Journal of Medical Chemistry 50, 59035911.

A.M. Giannetti (2011). From experimental design to validated hits a comprehensive walk-through of fragment lead identification using surface plasmon resonance. Methods in Enzymology 493, 169218.

S. Gong , G. Yoon , I. Jang , D. Bolser , P. Dafas , M. Schroeder , H. Choi , Y. Cho , K. Han , S. Lee , M. Lappe , L. Holm , S. Kim , D. Oh & J. Bhak (2005). PSIbase: a database of protein structural interactome map (PSIMAP). Bioinformatics 21, 25412543.

B.A. Grzybowski , A.V. Ishchenko , J. Shimada & E.I. Shakhnovich (2002). From knowledge-based potentials to combinatorial lead design in silico. Accounts of Chemical Research 35, 261269.

P.J. Hajduk & J. Greer (2007). A decade of fragment-based drug design: strategic advances and lessons learned. Nature Reviews. Drug Discovery 6, 211219.

P.J. Hajduk , J.R. Huth & S.W. Fesik (2005). Druggability indices for protein targets derived from NMR-based screening data. Journal of Medical Chemistry 48, 25182525.

P.J. Hajduk , E.T. Olejniczak & S.W. Fesik (1997). One-dimensional relaxation and diffusion-edited NMR methods for screening compounds that bind to macromolecules. Journal of the American Chemical Society 119, 12257–11226.

M.D. Hamalainen , A. Zhukov , M. Ivarsson , T. Fex , J. Gottfries , R. Karlsson & M. Bjorsne (2008). Label-free primary screening and affinity ranking of fragment libraries using parallel analysis of protein panels. Journal of Biomolecular Screening: The Official Journal of the Society for Biomolecular Screening 13, 202209.

M.M. Hann , A.R. Leach & G. Harper (2001). Molecular complexity and its impact on the probability of finding leads for drug discovery. Journal of Chemical Information and Computer Sciences 41, 856864.

M.J. Hartshorn , C.W. Murray , A. Cleasby , M. Frederickson , I.J. Tickle & H. Jhoti (2005). Fragment-based lead discovery using X-ray crystallography. Journal of Medical Chemistry 48, 403413.

M. Hendlich , F. Rippmann & G. Barnickel (1997). LIGSITE: automatic and efficient detection of potential small molecule-binding sites in proteins. Journal of Molecular Graphics & Modeling 15, 359363, 389.

H. Hermjakob , L. Montecchi-Palazzi , C. Lewington , S. Mudali , S. Kerrien , S. Orchard , M. Vingron , B. Roechert , P. Roepstorff , A. Valencia , H. Margalit , J. Armstrong , A. Bairoch , G. Cesareni , D. Sherman & R. Apweller (2004). IntAct: an open source molecular interaction database. Nucleic Acids Research 32, D452D455.

A.P. Higueruelo , A. Schreyer , G.R. Bickerton , W.R. Pitt , C.R. Groom & T.L. Blundell (2009). Atomic interactions and profile of small molecules disrupting protein–protein interfaces: the TIMBAL database. Chemistry Biology and Drug Design 74, 457467.

H. Hirai , H. Sootome , Y. Nakatsuru , K. Miyama , S. Taguchi , K. Tsujioka , Y. Ueno , H. Hatch , P.K. Majumder , B.S. Pan & H. Kotani (2010). MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Molecular Cancer and Therapeutics 9, 19561967.

G.A. Holdgate & W.H. Ward (2005). Measurements of binding thermodynamics in drug discovery. Drug Discovery Today 10, 15431550.

S.W. Homans (2004). NMR spectroscopy tools for structure-aided drug design. Angewandte Chemie International Edition 43, 290300.

A.L. Hopkins & C.R. Groom (2002). The druggable genome. Nature Reviews Drug Discovery 1, 727730.

A.L. Hopkins , C.R. Groom & A. Alex (2004). Ligand efficiency: a useful metric for lead selection. Drug Discovery Today 9, 430431.

N. Howard , C. Abell , W. Blakemore , G. Chessari , M. Congreve , S. Howard , H. Jhoti , C.W. Murray , L.C. Seavers & R.L. Van Montfort (2006). Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors. Journal of Medical Chemistry 49, 13461355.

R.E. Hubbard , B. Davis , I. Chen & M.J. Drysdale (2007). The SeeDs approach: integrating fragments into drug discovery. Current Topics in Medicinal Chemistry 7, 15681581.

R.E. Hubbard & J.B. Murray (2011). Experiences in fragment-based lead discovery. Methods in Enzymology 493, 509531.

A.W. Hung , A. Ramek , Y. Wang , T. Kaya , J.A. Wilson , P.A. Clemons & D.W. Young (2011). Organic synthesis toward small-molecule probes and drugs special feature: route to three-dimensional fragments using diversity-oriented synthesis. Proceedings of the National Academy of Sciences of the United States of America 108, 67996804.

A.W. Hung , H.L. Silvestre , S. Wen , A. Ciulli , T.L. Blundell & C. Abell (2009). Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase. Angewandte Chemie International Edition 48, 84528456.

J.J. Irwin & B.K. Shoichet (2005). ZINC – a free database of commercially available compounds for virtual screening. Journal of Chemical Information Model 45, 177182.

E.R. Jefferson , T.P. Walsh , T.J. Roberts & G.J. Barton (2007). SNAPPI-DB: a database and API of structures, iNterfaces and alignments for protein–protein interactions. Nucleic Acids Research 35 (Database issue), D580D589.

L.D. Jennings , K.W. Foreman , T.S. Rush III, D.H. Tsao , L. Mosyak , S.L. Kincaid , M.N. Sukhdeo , A.G. Sutherland , W. Ding , C.H. Kenny , C.L. Sabus , H. Liu , E.G. Dushin , S.L. Moghazeh , P. Labthavikul , P.J. Petersen , M. Tuckman , S.A. Haney & A.V. Ruzin (2004a). Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of ZipA–FtsZ interaction. Bioorganic and Medicinal Chemistry 12, 51155131.

L.D. Jennings , K.W. Foreman , T.S. Rush III, D.H. Tsao , L. Mosyak , Y. Li , M.N. Sukhdeo , W. Ding , E.G. Dushin , C.H. Kenny , S.L. Moghazeh , P.J. Petersen , A.V. Ruzin , M. Tuckman & A.G. Sutherland (2004b). Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the ZipA–FtsZ interaction. Bioorganic and Medicinal Chemistry Lett 14, 14271431.

A.L. Jochim & P.S. Arora (2009). Assessment of helical interfaces in protein–protein interactions. Molecular Biosystems 5, 924926.

A.L. Jochim & P.S. Arora (2010). Systematic analysis of helical protein interfaces reveals targets for synthetic inhibitors. ACS Chemical Biology 5, 919923.

H. Jubb , A. Higueruelo , A. Winter & T. Blundell (2012). Structural biology and drug discovery for protein–protein interactions. Trends in Pharmacological Sciences 33, 241248.

Y. Kalidas & N. Chandra (2008). PocketDepth: a new depth based algorithm for identification of ligand binding sites in proteins. Journal of Structurall Biology 161, 3142.

C.H. Kenny , W. Ding , K. Kelleher , S. Benard , E.G. Dushin , A.G. Sutherland , L. Mosyak , R. Kriz & G. Ellestad (2003). Development of a fluorescence polarization assay to screen for inhibitors of the FtsZ/ZipA interaction. Analytical Biochemistry 323, 224233.

G.M. Keseru & G.M. Makara (2009). The influence of lead discovery strategies on the properties of drug candidates. Nature Reviews. Drug Discovery 8, 203212.

O. Keskin , B. Ma , K. Rogale , K. Gunasekaran & R. Nussinov (2005). Protein-protein interactions: organization, cooperativity and mapping in a bottom-up systems biology approach. Physical Biology 2, S2435.

T.S. Khurana & K.E. Davies (2003). Pharmacological strategies for muscular dystrophy. Nature Reviews Drug Discovery 2, 379390.

O. Kim , Y. Jeong , H. Lee , S.S. Hong & S. Hong (2011). Design and synthesis of imidazopyridine analogues as inhibitors of phosphoinositide 3-kinase signaling and angiogenesis. Journal of Medical Chemistry 54, 24552466.

M. Kobayashi , K. Retra , F. Figaroa , J.G. Hollander , E. Ab , R.J. Heetebrij , H. Irth & G. Siegal (2010). Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification. Journal of Biomolecular Screening: The Official Journal of the Society for Biomolecular Screening 15, 978989.

T. Kortemme & D. Baker (2002). A simple physical model for binding energy hot spots in protein–protein complexes. Proceedings of the National Academy of Sciences of the United States of America 99, 1411614121.

E. Krissinel & K. Henrick (2007). Inference of macromolecular assemblies from crystalline state. Journal of Molecular Biology 372, 774797.

I.D. Kuntz , K. Chen , K.A. Sharp & P.A. Kollman (1999). The maximal affinity of ligands. Proceedings of the National Academy of Sciences of the United States of America 96, 999710002.

K. Lage , E.O. Karlberg , Z.M. Storling , P.I. Olason , A.G. Pedersen , O. Rigina , A.M. Hinsby , Z. Tumer , F. Pociot , N. Tommerup , Y. Moreau & S. Brunak (2007). A human phenome–interactome network of protein complexes implicated in genetic disorders. Nature Biotechnology 25, 309316.

G. Lauri & P.A. Bartlett (1994). CAVEAT: a program to facilitate the design of organic molecules. Journal of Computer-Aided Molecular Design 8, 5166.

A.T. Laurie & R.M. Jackson (2005). Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites. Bioinformatics 21, 19081916.

S.H. Lawrence , U.D. Ramirez , L. Tang , F. Fazliyez , L. Kundrat , G.D. Markham & E.K. Jaffe (2008). Shape shifting leads to small-molecule allosteric drug discovery. Chemistry & Biology 15, 586596.

V. Le Guilloux , P. Schmidtke & P. Tuffery (2009). Fpocket: an open source platform for ligand pocket detection. BMC Bioinformatics 10, 168.

S. Leavitt & E. Freire (2001). Direct measurement of protein binding energetics by isothermal titration calorimetry. Current Opinion in Structural Biology 11, 560566.

G.M. Lee & C.S. Craik (2009). Trapping moving targets with small molecules. Science 324, 213215.

S. Lee , A. Brown , W. Pitt , A. Higueruelo , S. Gong , G. Bickerton , A. Schreyer , D. Tanramluk , A. Baylay & T. Blundell (2009). Structural interactomics: informatics approaches to aid the interpretation of genetic variation and the development of novel therapeutics. Molecular Biosystems. 5, 14561472.

C.A. Lepre (2011). Practical aspects of NMR-based fragment screening. Methods in Enzymology 493, 219239.

C.A. Lepre , J.M. Moore & J.W. Peng (2004). Theory and applications of NMR-based screening in pharmacautical research. Chemical Reviews 104, 36413675.

S.M. Leung , G. Senisterra , K.P. Ritchie , S.E. Sadis , J.R. Lepock & L.E. Hightower (1996). Thermal activation of the bovine Hsc70 molecular chaperone at physiological temperatures: physical evidence of a molecular thermometer. Cell Stress Chaperones 1, 7889.

J. Li & Q. Liu (2009). ‘Double water exclusion’: a hypothesis refining the O-ring theory for the hot spots at protein interfaces. Bioinformatics 25, 743750.

E. Liepinsh & G. Otting (1997). Organic solvents identify specific ligand binding sites on protein surfaces. Nature Biotechnology 15, 264268.

C.A. Lipinski , F. Lombardo , B.W. Dominy & P.J. Feeney (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 46, 326.

S. Lise , D. Buchan , M. Pontil & D.T. Jones (2011). Predictions of hot spot residues at protein–protein interfaces using support vector machines. PLoS ONE 6, e16774.

C.C. Liu & P.G. Schultz (2010). Adding new chemistries to the genetic code. Annual Review of Biochemistry, 79, 413444.

G. Liu , J.R. Huth , E.T. Olejniczak , R. Mendoza , P. Devries , S. Leitza , E.B. Reilly , G.F. Okasinski , S.W. Fesik & T.W. Von Geldern (2001). Novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 2. Mechanism of inhibition and structure-based improvement of pharmaceutical properties. Journal of Medical Chemistry 44, 12021210.

M.C. Lo , A. Aulabaugh , G. Jin , R. Cowling , J. Bard , M. Malamas & G. Ellestad (2004). Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery. Analytical Biochemistry 332, 153159.

Q. Luo , P. Pagel , B. Vilne & D. Frishman (2011). DIMA 3.0: domain interaction map. Nucleic Acids Research 39 (Database issue), D724D729.

C. Mattos & D. Ringe (1996). Locating and characterizing binding sites on proteins. Nature Biotechnology 14, 595599.

M. Mayer & B. Meyer (1999). Characterization of ligand binding by saturation transfer difference NMR spectroscopy. Angewandte Chemie International Edition 38, 17841788.

L.M. Meireles , A.S. Domling & C.J. Camacho (2010). ANCHOR: a web server and database for analysis of protein–protein interaction binding pockets for drug discovery. Nucleic Acids Research 38(Web Server issue), W407W411.

B. Meyer & T. Peters (2003). NMR spectroscopy techniques for screening and identifying ligand binding to protein receptors. Angewandte Chemie International Edition 42, 864890.

R.E. Moellering , M. Cornejo , T.N. Davis , C. Del Bianco , J.C. Aster , S.C. Blacklow , A.L. Kung , D.G. Gilliland , G.L. Verdine & J.E. Bradner (2009). Direct inhibition of the NOTCH transcription factor complex. Nature 462, 182188.

S.W. Muchmore , J. Olson , R. Jones , J. Pan , M. Blum , J. Greer , S.M. Merrick , P. Magdalinos & V.L. Nienaber (2000). Automated crystal mounting and data collection for protein crystallography. Structure 8, R243R246.

M. Morita , S. Nakamura & K. Shimizu (2008). Highly accurate method for ligand-binding site prediction in unbound state (apo) protein structures. Proteins 73, 468479.

C.W. Murray & T.L. Blundell (2010). Structural biology in fragment-based drug design. Current Opinion in Structural Biology 20, 497507.

I. Navratilova , J. Besnard & A.L. Hopkins (2011). Screening for GPCR ligands using surface plasmon resonance. ACS Medicinal Chemistry Letters 2, 549554.

V.L. Nienaber , P.L. Richardson , V. Klighofer , J.J. Bouska , V.L. Giranda & J. Greer (2000). Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nature Biotechnology 18, 11051108.

I.M. Nooren & J.M. Thornton (2003). Structural characterisation and functional significance of transient protein–protein interactions. Journal of Molecular Biology 325, 9911018.

H. Nordin , M. Jungnelius , R. Karlsson & O.P. Karlsson (2005). Kinetic studies of small molecule interactions with protein kinases using biosensor technology. Analytical Biochemistry 340, 359368.

U. Ogmen , O. Keskin , A.S. Aytuna , R. Nussinov & A. Gursoy (2005). PRISM: protein interactions by structural matching. Nucleic Acids Research 33 (Web Server issue), W331W336.

T.S. Olsson , M.A. Williams , W.R. Pitt & J.E. Ladbury (2008). The thermodynamics of protein–ligand interaction and solvation: insights for ligand design. Journal of Molecular Biology 384, 10021017.

T. Oltersdorf , S.W. Elmore , A.R. Shoemaker , R.C. Armstrong , D.J. Augeri , B.A. Belli , M. Bruncko , T.L. Deckwerth , J. Dinges , P.J. Hajduk , M.K. Joseph , S. Kitada , S.J. Korsmeyer , A.R. Kunzer , A. Letai , C. Li , M.J. Mitten , D.G. Nettesheim , S. Ng , P.M. Nimmer , J.M. O'CONNOR , A. Oleksijew , A.M. Petros , J.C. Reed , W. Shen , S.K. Tahir , C.B. Thompson , K.J. Tomaselli , B. Wang , M.D. Wendt , H. Zhang , S.W. Fesik & S.H. Rosenberg (2005). An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677681.

M.W. Pantolino , E.C. Petrella , J.D. Kwasnoski , V.S. Lobanov , J. Myslik , E. Graf , T. Carver , E. Asel , B.A. Springer , P. Lane & F.R. Salemme (2001). High-density miniaturized thermal shift assays as a general strategy for drug discovery. Journal of Biomolecular Screening 6, 429440.

S. Orchard , S. Kerrien , P. Jones , A. Ceol , A. Chatr-Aryamontri , L. Salwinski , J. Nerothin & H. Hermjakob (2007). Submit your interaction data the IMEx way: a step by step guide to trouble-free deposition. Proteomics 7 (Suppl. 1), 2834.

L. Pellegrini , D.S. Yu , T. Lo , S. Anand , M. Lee , T.L. Blundell & A.R. Venkitaraman (2002). Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature 420, 287293.

S. Perot , O. Sperandio , M.A. Miteva , A.C. Camproux & B.O. Villoutreix (2010). Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery. Drug Discovery Today 15, 656667.

S. Perspicace , D. Banner , J. Benz , F. Muller , D. Schlatter & W. Huber (2009). Fragment-based screening using surface plasmon resonance technology. Journal of Biomolecular Screening: The Official Journal of the Society for Biomolecular Screening 14, 337349.

A.M. Petros , J. Dinges , D.J. Augeri , S.A. Baumeister , D.A. Betebenner , M.G. Bures , S.W. Elmore , P.J. Hajduk , M.K. Joseph , S.K. Landis , D.G. Nettesheim , S.H. Rosenberg , W. Shen , S. Thomas , X. Wang , I. Zanze , H. Zhang & S.W. Fesik (2006). Discovery of a potent inhibitor of the antiapoptotic protein Bcl-XL from NMR and parallel synthesis. Journal of Medicinal Chemistry 49, 656663.

M.M. Pierce , C.S. Raman & B.T. Nall (1999). Isothermal titration calorimetry of protein–protein interactions. Methods 19, 213221.

D. Rajamani , S. Thiel , S. Vajda & C.J. Camacho (2004). Anchor residues in protein–protein interactions. Proceedings of the National Academy of Sciences of the United States of America 101, 1128711292.

H. Razavi , S.K. Palaninathan , E.T. Powers , R.L. Wiseman , H.E. Purkey , N.N. Mohamedmohaideen , S. Deechongkit , K.P. Chiang , M.T. Dendle , J.C. Sacchettini & J.W. Kelly (2003). Benzoxazoles as transthyretin amyloid fibril inhibitors: synthesis, evaluation, and mechanism of action. Angewandte Chemie International Edition 42, 27582761.

C.H. Rohrig , C. Loch , J.Y. Guan , G. Siegal & M. Overhand (2007). Fragment-based synthesis and SAR of modified FKBP ligands: influence of different linking on binding affinity. Chem Med Chem 2, 10541070.

T.S. Rush 3rd, J.A. Grant , L. Mosyak & A. Nicholls (2005). A shape-based 3-D scaffold hopping method and its application to a bacterial protein–protein interaction. Journal of Medical Chemistry 48, 14891495.

K. Sasaki , S. Dockerill , D.A. Adamiak , I.J. Tickle & T. Blundell (1975). X-ray analysis of glucagon and its relationship to receptor binding. Nature 257, 751757.

G. Saxty , S.J. Woodhead , V. Berdini , T.G. Davies , M.L. Verdonk , P.G. Wyatt , R.G. Boyle , D. Barford , R. Downham , M.D. Garrett & R.A. Carr (2007). Identification of inhibitors of protein kinase B using fragment-based lead discovery. Journal of Medical Chemistry 50, 22932296.

P. Schmidtke & X. Barril (2010). Understanding and predicting druggability. A high-throughput method for detection of drug binding sites. Journal of Medical Chemistry 53, 58585867.

P. Schmidtke , C. Souaille , F. Estienne , N. Baurin & R.T. Kroemer (2010). Large-scale comparison of four binding site detection algorithms. Journal of Chemical Information Model 50, 21912200.

G. Schneider & U. Fechner (2005). Computer-based de novo design of drug-like molecules. Nature Reviews Drug Discovery 4, 649663.

R. Schwyzer , V.M. Kriwaczek , K. Baumann , H.-R. Haller , G. Wider & A.P. Wiltzius (1979). Hormone-receptor interactions: a study of the binding of hormone-substituted tobacco mosaic virus to membrane vesicles by dynamic light scattering and by transient electric bi-refringence. Pure and Applied Chemistry 51, 831835.

J. Segura & N. Fernandez-Fuentes (2011). PCRPi-DB: a database of computationally annotated hot spots in protein interfaces. Nucleic Acids Research 39 (Database issue), D755D760.

S.B. Shuker , P.J. Hajduk , R.P. Meadows & S.W. Fesik (1996). Discovering high-affinity ligands for proteins: SAR by NMR. Science 274, 15311534.

B.W. Sigurskjold (2000). Exact analysis of competition ligand binding by displacement isothermal titration calorimetry. Analytical Biochemistry 277, 260266.

P. Sledz , H. Zheng , K. Murzyn , M. Chruszcz , M.D. Zimmerman , M.D. Chordia , A. Joachimiak & W. Minor (2010). New surface contacts formed upon reductive lysine methylation: improving the probability of protein crystallization. Protein Science: A Publication of the Protein Society 19, 13951404.

P. Smialowski , P. Pagel , P. Wong , B. Brauner , I. Dunger , G. Fobo , G. Frishman , C. Montrone , T. Rattei , D. Frishman & A. Ruepp (2010). The Negatome database: a reference set of non-interacting protein pairs. Nucleic Acids Research 38 (Database issue), D540D544.

J.C. Spurlino (2011). Fragment screening purely with protein crystallography. Methods in Enzymology 493, 321356.

A. Stein , A. Ceol & P. Aloy (2011). 3did: identification and classification of domain-based interactions of known three-dimensional structure. Nucleic Acids Research 39 (Database issue), D718D723.

M.L. Stewart , E. Fire , A.E. Keating & L.D. Walensky (2010). The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nature Chemical Biology 6, 595601.

B.J. Stockman , M. Kothe , D. Kohls , L. Weibley , B.J. Connolly , A.L. Sheils , Q. Cao , A.C. Cheng , L. Yang , A.V. Kamath , Y.H. Ding & M.E. Charlton (2009). Identification of allosteric PIF-pocket ligands for PDK1 using NMR-based fragment screening and 1H-15N TROSY experiments. Chemical Biology and Drug Design 73, 179188.

K. Sugase , H.J. Dyson & P.E. Wright (2007). Mechanism of coupled folding and binding of an intrinsically disordered protein. Nature 447, 10211025.

N. Sugaya & T. Furuya (2011). Dr. PIAS: an integrative system for assessing the druggability of protein–protein interactions. BMC Bioinformatics 12, 50.

N. Sugaya & K. Ikeda (2009). Assessing the druggability of protein–protein interactions by a supervised machine-learning method. BMC Bioinformatics 10, 263.

A.G. Sutherland , J. Alvarez , W. Ding , K.W. Foreman , C.H. Kenny , P. Labthavikul , L. Mosyak , P.J. Petersen , T.S. Rush 3rd, A. Ruzin , D.H. Tsao & K.L. Wheless (2003). Structure-based design of carboxybiphenylindole inhibitors of the ZipA–FtsZ interaction. Organic and Biomolecular Chemistry 1, 41384140.

D. Szklarczyk , A. Franceschini , M. Kuhn , M. Simonovic , A. Roth , P. Minguez , T. Doerks , M. Stark , J. Muller , P. Bork , L.J. Jensen & C. Von Mering (2011). The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Research 39 (Database issue), D561D568.

J.D. Taylor , P.J. Gilbert , M.A. Williams , W.R. Pitt & J.E. Ladbury (2007). Identification of novel fragment compounds targeted against the pY pocket of v-Src SH2 by computational and NMR screening and thermodynamic evaluation. Proteins 67, 981990.

J. Teyra , M. Paszkowski-Rogacz , G. Anders & M.T. Pisabarro (2008). SCOWLP classification: structural comparison and analysis of protein binding regions. BMC Bioinformatics 9, 9.

C.D. Thanos , W.L. Delano & J.A. Wells (2006). Hot-spot mimicry of a cytokine receptor by a small molecule. Proceedings of the National Academy of Sciences of the United States of America 103, 1542215427.

D. Thompson , A. Denny , R. Nilakantan , C. Humblet , D. Joseph-Mccarthy & E. Feyfant (2008). CONFIRM: connecting fragments found in receptor molecules. Journal of Computer-Aided Molecular Design 22, 761772.

K.S. Thorn & A.A. Bogan (2001). ASEdb: a database of alanine mutations and their effects on the free energy of binding in protein interactions. Bioinformatics 17, 284285.

J.W. Tilley , L. Chen , D.C. Fry , S.D. Emerson , G.D. Powers , D. Biondi , T. Varnell , R. Trilles , R. Guthrie , F. Mennona , G. Kaplan , R.A. Lemahieu , M. Carson , R.-J. Han , C.-M. Liu , R. Palermo & G. Ju (1997). Identification of a small molecule inhibitor of the IL-2/IL-2Rα receptor interaction which binds to IL-2. Journal of the American Chemical Society 119, 75897590.

F.E. Torres , M.I. Recht , J.E. Coyle , R.H. Bruce & G. Williams (2010). Higher throughput calorimetry: opportunities, approaches and challenges. Current Opinion in Structural Biology 20, 598605.

P. Traczewski & L. Rudnicka (2011). Treatment of systemic lupus erythematosus with epratuzumab. British Journal of Clinical Pharmacology 71, 175182.

D.H. Tsao , A.G. Sutherland , L.D. Jennings , Y. Li , T.S. Rush III, J.C. Alvarez , W. Ding , E.G. Dushin , R.G. Dushin , S.A. Haney , C.H. Kenny , A.K. Malakian , R. Nilakantan & L. Mosyak (2006). Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design. Bioorganic and Medicinal Chemistry 14, 79537961.

N. Tuncbag , G. Kar , O. Keskin , A. Gursoy & R. Nussinov (2009). A survey of available tools and web servers for analysis of protein–protein interactions and interfaces. Briefings in Bioinformatics 10, 217232.

A.L. Turinsky , S. Razick , B. Turner , I.M. Donaldson & S.J. Wodak (2011). Interaction databases on the same page. Nature Biotechnology 29, 391393.

W.B. Turnbull & A.H. Daranas (2003). On the value of c: can low affinity systems be studied by isothermal titration calorimetry? Journal of the American Chemical Society 125, 1485914866.

A. Tversky (1977). Features of Similarity. Psychological Reviews 84, 327352.

M. Vedadi , F.H. Niesen , A. Allali-Hassani , O.Y. Fedorov , P.J. Finerty Jr., G.A. Wasney , R. Yeung , C. Arrowsmith , L.J. Ball , H. Berglund , R. Hui & B.D. Marsden (2006). Chemical screening methods to identify ligands that promote protein stability, protein crystallization, and structure determination. Proceedings of the National Academy of Sciences of the United States of America 103, 1583515840.

A. Velazquez-Campoy , Y. Kiso & E. Freire (2001). The binding energetics of first- and second-generation HIV-1 protease inhibitors: implications for drug design. Archives of Biochemistry and Biophysics 390, 169175.

A. Velazquez-Campoy , M.J. Todd & E. Freire (2000). HIV-1 protease inhibitors: enthalpic versus entropic optimization of the binding affinity. Biochemistry 39, 22012207.

K. Venkatesan , J.F. Rual , A. Vazquez , U. Stelzl , I. Lemmens , T. Hirozane-Kishikawa , T. Hao , M. Zenkner , X. Xin , K.I. Goh , M.A. Yildirim , N. Simonis , K. Heinzmann , F. Gebreab , J.M. Sahalie , S. Cevik , C. Simon , A.S. De Smet , E. Dann , A. Smolyar , A. Vinayagam , H. Yu , D. Szeto , H. Borick , A. Dricot , N. Klitgord , R.R. Murray , C. Lin , M. Lalowski , J. Timm , K. Rau , C. Boone , P. Braun , M.E. Cusick , F.P. Roth , D.E. Hill , J. Tavernier , E.E. Wanker , A.L. Barabasi & M. Vidal (2009). An empirical framework for binary interactome mapping. Nature Methods 6, 8390.

H.M. Vinkers , M.R. De Jonge , F.F.D. Daeyaert , J. Heeres , L.M.H. Koymans , J.H. Van Lenthe , P.J. Lewi , H. Timmerman , K. Van Aken & P.A.J. Janssen (2003). SYNOPSIS: SYNthesize and OPtimize System in Silico. Journal of Medicinal Chemistry 46, 27652773.

T.T. Waldron & K.P. Murphy (2003). Stabilization of proteins by ligand binding: application to drug screening and determination of unfolding energetics. Biochemistry 42, 50585064.

L. Wang & P.G. Schultz (2004). Expanding the genetic code. Angewandte Chemie International Edition 44, 3466.

Z.X. Wang (1995). An exact mathematical expression for describing competitive binding of two different ligands to a protein molecule. FEBS Letters 360, 111114.

J. Wells & C. Mcclendon (2007). Reaching for high-hanging fruit in drug discovery at protein–protein interfaces. Nature 450, 10011009.

M.D. Wendt , C. Sun , A. Kunzer , D. Sauer , K. Sarris , E. Hoff , L. Yu , D.G. Nettesheim , J. Chen , S. Jin , K.M. Comess , Y. Fan , S.N. Anderson , B. Isaac , E.T. Olejniczak , P.J. Hajduk , S.H. Rosenberg & S.W. Elmore (2007). Discovery of a novel small molecule binding site of human survivin. Bioorganic and Medicinal Chemistry Lett 17, 31223129.

A.J. Wilson (2009). Inhibition of protein–protein interactions using designed molecules. Chemical Society Reviews 38, 32893300.

C. Winter , A. Henschel , W.K. Kim & M. Schroeder (2006). SCOPPI: a structural classification of protein–protein interfaces. Nucleic Acids Research 34(Database issue), D310D314.

T. Wiseman , S. Williston , J.F. Brandts & L.N. Lin (1989). Rapid measurement of binding constants and heats of binding using a new titration calorimeter. Analytical Biochemistry 179, 131137.

P.E. Wright & H.J. Dyson (1999). Intrinsically unstructured proteins: re-assessing the protein structure–function paradigm. Journal of Molecular Biology 293, 321331.

P.E. Wright & H.J. Dyson (2009). Linking folding and binding. Current Opinion in Structural Biology 19, 3138.

W.I. Wu , W.C. Voegtli , H.L. Sturgis , F.P. Dizon , G.P. Vigers & B.J. Brandhuber (2010). Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. PLoS ONE 5, e12913.

I. Xenarios , D.W. Rice , L. Salwinski , M.K. Baron , E.M. Marcotte & D. Eisenberg (2000). DIP: the database of interacting proteins. Nucleic Acids Research 28, 289291.

Y. Xiang , B. Hirth , G. Asmussen , H.P. Biemann , K.A. Bishop , A. Good , M. Fitzgerald , T. Gladysheva , A. Jain , K. Jancsics , J. Liu , M. Metz , A. Papoulis , R. Skerlj , J.D. Stepp & R.R. Wei (2011). The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors. Bioorganic and Medicinal Chemistry Lett 21, 30503056.

Q. Xu , A. Canutescu , Z. Obradovic & R.L. Dunbrack Jr., ( 2006). ProtBuD: a database of biological unit structures of protein families and superfamilies. Bioinformatics 22, 28762882.

S. Yellaboina , A. Tasneem , D.V. Zaykin , B. Raghavachari & R. Jothi (2011). DOMINE: a comprehensive collection of known and predicted domain–domain interactions. Nucleic Acids Research 39(Database issue), D730D735.

H. Yin & A.D. Hamilton (2004). Terephthalamide derivatives as mimetics of the helical region of Bak peptide target Bcl-XL protein. Bioorganic and Medicinal Chemistry Lett 14, 13751379.

A.B. Young (2003). Huntingtin in health and disease. Journal of Clinical Investigation 111, 299302.

T.S. Young & P.G. Schultz (2010). Beyond the canonical 20 amino acids: expanding the genetic lexicon. The Journal of Biological Chemistry 285, 1103911044.

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