Hostname: page-component-78c5997874-4rdpn Total loading time: 0 Render date: 2024-11-17T21:22:12.137Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  13 September 2012

Anja Winter ,
Alicia P. Higueruelo ,
May Marsh ,
Anna Sigurdardottir ,
Will R Pitt  and
Tom L. Blundell
Anja Winter
Affiliation:
Department of Biochemistry, University of Cambridge, Cambridge CB1 2GA, UK
Alicia P. Higueruelo
Affiliation:
Department of Biochemistry, University of Cambridge, Cambridge CB1 2GA, UK
May Marsh
Affiliation:
Department of Biochemistry, University of Cambridge, Cambridge CB1 2GA, UK
Anna Sigurdardottir
Affiliation:
Department of Biochemistry, University of Cambridge, Cambridge CB1 2GA, UK
Will R Pitt
Affiliation:
Department of Biochemistry, University of Cambridge, Cambridge CB1 2GA, UK Department of Medicinal Chemistry, UCB Pharma, Slough SL1 3WE, UK
Tom L. Blundell*
Affiliation:
Department of Biochemistry, University of Cambridge, Cambridge CB1 2GA, UK
*
*Author for correspondence: Tom Blundell, The University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. Tel:+44(0)1223 333628; Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

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.

Type
Review Article
Information
Quarterly Reviews of Biophysics , Volume 45 , Issue 4 , November 2012 , pp. 383 - 426
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

8. References

Abdel-Rahman, N., Martinez-Arias, A. & Blundell, T.L. (2011). Probing the druggability of protein–protein interactions: targeting the Notch1 receptor ankyrin domain using a fragment-based approach. Biochemical Society Transactions 39, 1327–1333.CrossRefGoogle ScholarPubMed
Barelier, S., Pon, J., Marcillat, O., Lancelin, J.M. & Krimm, I. (2010). Fragment-based deconstruction of Bcl-XL inhibitors. Journal of Medical Chemistry 53, 2577–2588.CrossRefGoogle ScholarPubMed
Bernal, F., Wade, M., Godes, M., Davis, T.N., Whitehead, D.G., Kung, A.L., Wahl, G.M. & Walensky, L.D. (2010). A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell 18, 411–422.CrossRefGoogle ScholarPubMed
Best, J.L., Amezcua, C.A., Mayr, B., Flechner, L., Murawsky, C.M., Emerson, B., Zor, T., Gardner, K.H. & Montminy, M. (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, 17622–17627.CrossRefGoogle ScholarPubMed
Bickerton, G.R. (2009). Molecular characterization and evolutionary plasticity of protein–protein interfaces, University of Cambridge.Google Scholar
Bickerton, G.R., Higueruelo, A.P. & Blundell, T.L. (2011). Comprehensive, atomic-level characterization of structurally characterized protein–protein interactions: the PICCOLO database. BMC Bioinformatics 12, 313.CrossRefGoogle ScholarPubMed
Blundell, T. (1979). Conformation and molecular biology of polypeptide hormones II. Glucagon. Trends in Biochemical Sciences 4, 80–83.CrossRefGoogle Scholar
Blundell, T. & Wood, S. (1982). The conformation, flexibility and dynamics of polypeptide hormones. Annual Review of Biochemistry 51, 123–154.CrossRefGoogle ScholarPubMed
Blundell, T.L., Burke, D.F., Chirgadze, D., Dhanaraj, V., Hyvonen, M., Innis, C.A., Parisini, E., Pellegrini, L., Sayed, M. & Sibanda, B.L. (2000). Protein–protein interactions in receptor activation and intracellular signalling. Biological Chemistry 381, 955–959.CrossRefGoogle ScholarPubMed
Blundell, T.L., Jhoti, H. & Abell, C. (2002). High-throughput crystallography for lead discovery in drug design. Nature Reviews Drug Discovery 1, 45–54.CrossRefGoogle ScholarPubMed
Blundell, T.L., Sibanda, B.L., Montalvao, R.W., Brewerton, S., Chelliah, V., Worth, C.L., Harmer, N.J., Davies, O. & Burke, D. (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, 413–423.CrossRefGoogle ScholarPubMed
Boehr, D.D., Nussinov, R. & Wright, P.E. (2009). The role of dynamic conformational ensembles in biomolecular recognition. Nature Chemical Biology 5, 789–796.CrossRefGoogle ScholarPubMed
Bogan, A.A. & Thorn, K.S. (1998). Anatomy of hot spots in protein interfaces. Journal of Molecular Biology 280, 1–9.CrossRefGoogle ScholarPubMed
Bonda, D.J., Lee, H.P., Lee, H.G., Friedlich, A.L., Perry, G., Zhu, X. & Smith, M.A. (2010). Novel therapeutics for Alzheimer's disease: an update. Current Opinion in Drug Discovery and Development 13, 235–246.Google ScholarPubMed
Bordner, A.J. (2009). Predicting protein–protein binding sites in membrane proteins. BMC Bioinformatics 10, 312.CrossRefGoogle ScholarPubMed
Bourgeas, R., Basse, M.J., Morelli, X. & Roche, P. (2010). Atomic analysis of protein–protein interfaces with known inhibitors: the 2P2I database. PLoS ONE 5, e9598.CrossRefGoogle ScholarPubMed
Boyden, S. (1962). The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. Journal of Experimental Medicine 115, 453–466.CrossRefGoogle ScholarPubMed
Brandts, J.F. & Lin, L.N. (1990). Study of strong to ultratight protein interactions using differential scanning calorimetry. Biochemistry 29, 6927–6940.CrossRefGoogle ScholarPubMed
Braun, W., Wider, G., Lee, K.H. & Wuthrich, K. (1983). Conformation of glucagon in a lipid–water interphase by 1H nuclear magnetic resonance. Journal of Molecular Biology 169, 921–948.CrossRefGoogle Scholar
Bruncko, M., Oost, T.K., Belli, B.A., Ding, H., Joseph, M.K., Kunzer, A., Martineau, D., Mcclellan, W.J., Mitten, M., Ng, S.C., Nimmer, P.M., Oltersdorf, T., Park, C.M., Petros, A.M., Shoemaker, A.R., Song, X., Wang, X., Wendt, M.D., Zhang, H., Fesik, S.W., Rosenberg, S.H. & Elmore, S.W. (2007). Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-XL. Journal of Medical Chemistry 50, 641–662.CrossRefGoogle ScholarPubMed
Buerger, C. & Groner, B. (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, 669–675.CrossRefGoogle ScholarPubMed
Cardinale, D., Salo-Ahen, O.M., Ferrari, S., Ponterini, G., Cruciani, G., Carosati, E., Tochowicz, A.M., Mangani, S., Wade, R.C. & Costi, M.P. (2010). Homodimeric enzymes as drug targets. Current Medicinal Chemistry 17, 826–846.CrossRefGoogle ScholarPubMed
Carr, R. & Jhoti, H. (2002). Structure-based screening of low-affinity compounds. Drug Discovery Today 7, 522–527.CrossRefGoogle ScholarPubMed
Carr, R.A., Congreve, M., Murray, C.W. & Rees, D.C. (2005). Fragment-based lead discovery: leads by design. Drug Discovery Today 10, 987–992.CrossRefGoogle ScholarPubMed
Celej, M.S., Montich, G.G. & Fidelio, G.D. (2003). Protein stability induced by ligand binding correlates with changes in protein flexibility. Protein Science: A Publication of the Protein Society 12, 1496–1506.CrossRefGoogle ScholarPubMed
Chakrabarti, P. & Bhattacharyya, R. (2007). Geometry of nonbonded interactions involving planar groups in proteins. Progress in Biophysics and Molecular Biology 95, 83–137.CrossRefGoogle ScholarPubMed
Chatr-Aryamontri, A., Ceol, A., Palazzi, L.M., Nardelli, G., Schneider, M.V., Castagnoli, L. & Cesareni, G. (2007). MINT: the Molecular INTeraction database. Nucleic Acids Research 35, D572–D574.CrossRefGoogle ScholarPubMed
Chen, J., Zheng, X.F., Brown, E.J. & Schreiber, S.L. (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, 4947–4951.CrossRefGoogle ScholarPubMed
Chen, Y.C., Chen, H.C. & Yang, J.M. (2006). DAPID: a 3D-domain annotated protein–protein interaction database. Genome Informatics 17, 206–215.Google ScholarPubMed
Choi, J., Chen, J., Schreiber, S.L. & Clardy, J. (1996). Structure of the FKBP12–rapamycin complex interacting with the binding domain of human FRAP. Science 273, 239–242.CrossRefGoogle ScholarPubMed
Choi, Y.S., Hur, J., Lee, H.K. & Jeong, S. (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, 1415–1421.CrossRefGoogle ScholarPubMed
Chung, S., Parker, J.B., Bianchet, M., Amzel, L.M. & Stivers, J.T. (2009). Impact of linker strain and flexibility in the design of a fragment-based inhibitor. Nature Chemical Biology 5, 407–413.CrossRefGoogle ScholarPubMed
Cimmperman, P., Baranauskiene, L., Jachimoviciute, S., Jachno, J., Torresan, J., Michailoviene, V., Matuliene, J., Sereikaite, J., Bumelis, V. & Matulis, D. (2008). A quantitative model of thermal stabilization and destabilization of proteins by ligands. Biophysics Journal 95, 3222–3231.CrossRefGoogle ScholarPubMed
Ciulli, A., Williams, G., Smith, A.G., Blundell, T.L. & Abell, C. (2006). Probing hot spots at protein-ligand binding sites: a fragment-based approach using biophysical methods. Journal of Medical Chemistry 49, 4992–5000.CrossRefGoogle ScholarPubMed
Clackson, T. & Wells, J.A. (1995). A hot spot of binding energy in a hormone–receptor interface. Science 267, 383–386.CrossRefGoogle Scholar
Cole, D.C., Olland, A.M., Jacob, J., Brooks, J., Bursavich, M.G., Czerwinski, R., Declercq, C., Johnson, M., Joseph-Mccarthy, D., Ellingboe, J.W., Lin, L., Nowak, P., Presman, E., Strand, J., Tam, A., Williams, C.M., Yao, S., Tsao, D.H. & Fitz, L.J. (2010). Identification and characterization of acidic mammalian chitinase inhibitors. Journal of Medical Chemistry 53, 6122–6128.CrossRefGoogle ScholarPubMed
Congreve, M., Carr, R., Murray, C. & Jhoti, H. (2003). A ‘rule of three’ for fragment-based lead discovery? Drug Discovery Today 8, 876–877.CrossRefGoogle ScholarPubMed
Congreve, M., Chessari, G., Tisi, D. & Woodhead, A.J. (2008). Recent developments in fragment-based drug discovery. Journal of Medical Chemistry 51, 3661–3680.CrossRefGoogle ScholarPubMed
Congreve, M., Murray, C.W. & Blundell, T.L. (2005). Structural biology and drug discovery. Drug Discovery Today 10, 895–907.CrossRefGoogle ScholarPubMed
Congreve, M., Rich, R.L., Myszka, D.G., Figaroa, F., Siegal, G. & Marshall, F.H. (2011). Fragment screening of stabilized G-protein-coupled receptors using biophysical methods. Methods in Enzymology 493, 115–136.CrossRefGoogle ScholarPubMed
D'arcy, A., Villard, F. & Marsh, M. (2007). An automated microseed matrix-screening method for protein crystallization. Acta Crystallographica, Section D, Biological Crystallography 63(Pt 4), 550–554.CrossRefGoogle ScholarPubMed
Dalvit, C., Pevarello, P., Tato, M., Veronesi, M., Vulpetti, A. & Sundstrom, M. (2000). Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water. Journal of Biomolecular NMR 18, 65–68.CrossRefGoogle ScholarPubMed
Davies, T.G., van Montfort, R.L.M., Williams, G. & Jhoti, H. (2006). Pyramid: an integrated platform for fragment-based drug discovery. In Fragment-based Approaches in Drug Discovery, pp. 193–214. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA.CrossRefGoogle Scholar
Davis, F.P. & Sali, A. (2005). PIBASE: a comprehensive database of structurally defined protein interfaces. Bioinformatics 21, 1901–1907.CrossRefGoogle ScholarPubMed
Davis, F.P. & Sali, A. (2010). The overlap of small molecule and protein binding sites within families of protein structures. PLoS Computational Biology 6, e1000668.CrossRefGoogle ScholarPubMed
Dean, P.M., Firth-Clark, S., Harris, W., Kirton, S.B. & Todorov, N.P. (2006). SkelGen: a general tool for structure-based de novo ligand design. Expert Opinion on Drug Discovery 1, 179–189.CrossRefGoogle ScholarPubMed
Del Sol, A. & O'MEARA, P. (2005). Small-world network approach to identify key residues in protein–protein interaction. Proteins 58, 672–682.CrossRefGoogle ScholarPubMed
Dey, F. & Caflisch, A. (2008). Fragment-based de novo ligand design by multiobjective evolutionary optimization. Journal of Chemical Information Modeling 48, 679–690.CrossRefGoogle ScholarPubMed
Dorr, P., Westby, M., Dobbs, S., Griffin, P., Irvine, B., Macartney, M., Mori, J., Rickett, G., Smith-Burchnell, C., Napier, C., Webster, R., Armour, D., Price, D., Stammen, B., Wood, A. & Perros, M. (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, 4721–4732.CrossRefGoogle ScholarPubMed
Dou, Y., Baisnee, P.F., Pollastri, G., Pecout, Y., Nowick, J. & Baldi, P. (2004). ICBS: a database of interactions between protein chains mediated by beta-sheet formation. Bioinformatics 20, 2767–2777.CrossRefGoogle ScholarPubMed
Douguet, D. (2010). e-LEA3D: a computational-aided drug design web server. Nucleic Acids Research 38(Web Server issue), W615–W621.CrossRefGoogle ScholarPubMed
Douguet, D., Munier-Lehmann, H., Labesse, G. & Pochet, S. (2005). LEA3D: a computer-aided ligand design for structure-based drug design. Journal of Medical Chemistry 48, 2457–2468.CrossRefGoogle ScholarPubMed
Durrant, J., Amaro, R. & Mccammon, J. (2009). AutoGrow: a novel algorithm for protein inhibitor design. Chemical Biology & Drug Design 73, 168–178.CrossRefGoogle ScholarPubMed
Dyson, H.J. & Wright, P.E. (2002). Coupling of folding and binding for unstructured proteins. Current Opinion in Structural Biology 12, 54–60.CrossRefGoogle ScholarPubMed
Edfeldt, F.N., Folmer, R.H. & Breeze, A.L. (2011). Fragment screening to predict druggability (ligandability) and lead discovery success. Drug Discovery Today 16, 284–287.CrossRefGoogle ScholarPubMed
Edink, E., Rucktooa, P., Retra, K., Akdemir, A., Nahar, T., Zuiderveld, O., Van Elk, R., Janssen, E., Van Nierop, P., Van Muijlwijk-Koezen, J., Smit, A.B., Sixma, T.K., Leurs, R. & De Esch, I.J. (2011). Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis. Journal of the American Chemical Society 133, 5363–5371.CrossRefGoogle ScholarPubMed
Elinder, M., Geitmann, M., Gossas, T., Kallblad, P., Winquist, J., Nordstrom, H., Hamalainen, M. & Danielson, U.H. (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, 15–25.CrossRefGoogle ScholarPubMed
Erlanson, D.A., Braisted, A.C., Raphael, D.R., Randal, M., Stroud, R.M., Gordon, E.M. & Wells, J.A. (2000). Site-directed ligand discovery. Proceedings of the National Academy of Sciences of the United States of America 97, 9367–9372.CrossRefGoogle ScholarPubMed
Erlanson, D.A., Lam, J.W., Wiesmann, C., Luong, T.N., Simmons, R.L., Delano, W.L., Choong, I.C., Burdett, M.T., Flanagan, W.M., Lee, D., Gordon, E.M. & O'Brien, T. (2003). In situ assembly of enzyme inhibitors using extended tethering. Nature Biotechnology 21 308–314.CrossRefGoogle ScholarPubMed
Ferenczy, G.G. & Keserü, G.M. (2010). Enthalpic efficiency of ligand binding. Journal of Chemical Information Model 50, 1536–1541.CrossRefGoogle ScholarPubMed
Ferraris, D.M., Gherardi, E., Di, Y., Heinz, D.W. & Niemann, H.H. (2009). Ligand-mediated dimerization of the Met receptor tyrosine kinase by the bacterial invasion protein InlB. Journal of Molecular Biology 395, 522–532.CrossRefGoogle ScholarPubMed
Fischer, T.B., Arunachalam, K.V., Bailey, D., Mangual, V., Bakhru, S., Russo, R., Huang, D., Paczkowski, M., Lalchandani, V., Ramachandra, C., Ellison, B., Galer, S., Shapley, J., Fuentes, E. & Tsai, J. (2003). The binding interface database (BID): a compilation of amino acid hot spots in protein interfaces. Bioinformatics 19, 1453–1454.CrossRefGoogle Scholar
Fitzpatrick, P.A., Steinmetz, A.C., Ringe, D. & Klibanov, A.M. (1993). Enzyme crystal structure in a neat organic solvent. Proceedings of the National Academy of Sciences of the United States of America 90, 8653–8657.CrossRefGoogle Scholar
Fletcher, S. & Hamilton, A.D. (2005). Protein surface recognition and proteomimetics: mimics of protein surface structure and function. Current Opinion in Chemical Biology 9, 632–638.CrossRefGoogle ScholarPubMed
Fuller, J.C., Burgoyne, N.J. & Jackson, R.M. (2009). Predicting druggable binding sites at the protein–protein interface. Drug Discovery Today 14, 155–161.CrossRefGoogle ScholarPubMed
Gabadinho, J., Hall, D., Leonard, G., Gordon, E., Monaco, S. & Thibault, X. (2008). Remote access experiments at the macromolecular crystallography beamlines of the ESRF. Synchrotron Radiation News 21, 24–29.CrossRefGoogle Scholar
Gao, Y., Douguet, D., Tovchigrechko, A. & Vakser, I.A. (2007). DOCKGROUND system of databases for protein recognition studies: unbound structures for docking. Proteins 69, 845–851.CrossRefGoogle ScholarPubMed
Garrett, D.S., Seok, Y.J., Peterkofsky, A., Clore, G.M. & Gronenborn, A.M. (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, 4393–4398.CrossRefGoogle ScholarPubMed
Geitmann, M., Elinder, M., Seeger, C., Brandt, P., De Esch, I.J. & Danielson, U.H. (2011). Identification of a novel scaffold for allosteric inhibition of wild type and drug resistant HIV-1 reverse transcriptase by fragment library screening. Journal of Medicinal Chemistry 53, 699–708.CrossRefGoogle Scholar
Geschwindner, S., Olsson, L.L., Albert, J.S., Deinum, J., Edwards, P.D., De Beer, T. & Folmer, R.H. (2007). Discovery of a novel warhead against beta-secretase through fragment-based lead generation. Journal of Medical Chemistry 50, 5903–5911.CrossRefGoogle ScholarPubMed
Giannetti, A.M. (2011). From experimental design to validated hits a comprehensive walk-through of fragment lead identification using surface plasmon resonance. Methods in Enzymology 493, 169–218.CrossRefGoogle ScholarPubMed
Gong, S., Yoon, G., Jang, I., Bolser, D., Dafas, P., Schroeder, M., Choi, H., Cho, Y., Han, K., Lee, S., Lappe, M., Holm, L., Kim, S., Oh, D. & Bhak, J. (2005). PSIbase: a database of protein structural interactome map (PSIMAP). Bioinformatics 21, 2541–2543.CrossRefGoogle ScholarPubMed
Grzybowski, B.A., Ishchenko, A.V., Shimada, J. & Shakhnovich, E.I. (2002). From knowledge-based potentials to combinatorial lead design in silico. Accounts of Chemical Research 35, 261–269.CrossRefGoogle ScholarPubMed
Hajduk, P.J. (2006). Fragment-based drug design: how big is too big? Journal of Medical Chemistry 49, 6972–6976.CrossRefGoogle ScholarPubMed
Hajduk, P.J. & Greer, J. (2007). A decade of fragment-based drug design: strategic advances and lessons learned. Nature Reviews. Drug Discovery 6, 211–219.CrossRefGoogle ScholarPubMed
Hajduk, P.J., Huth, J.R. & Fesik, S.W. (2005). Druggability indices for protein targets derived from NMR-based screening data. Journal of Medical Chemistry 48, 2518–2525.CrossRefGoogle ScholarPubMed
Hajduk, P.J., Olejniczak, E.T. & Fesik, S.W. (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.CrossRefGoogle Scholar
Hamalainen, M.D., Zhukov, A., Ivarsson, M., Fex, T., Gottfries, J., Karlsson, R. & Bjorsne, M. (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, 202–209.CrossRefGoogle ScholarPubMed
Hann, M.M., Leach, A.R. & Harper, G. (2001). Molecular complexity and its impact on the probability of finding leads for drug discovery. Journal of Chemical Information and Computer Sciences 41, 856–864.CrossRefGoogle ScholarPubMed
Hartshorn, M.J., Murray, C.W., Cleasby, A., Frederickson, M., Tickle, I.J. & Jhoti, H. (2005). Fragment-based lead discovery using X-ray crystallography. Journal of Medical Chemistry 48, 403–413.CrossRefGoogle ScholarPubMed
Hendlich, M., Rippmann, F. & Barnickel, G. (1997). LIGSITE: automatic and efficient detection of potential small molecule-binding sites in proteins. Journal of Molecular Graphics & Modeling 15, 359–363, 389.CrossRefGoogle ScholarPubMed
Hermjakob, H., Montecchi-Palazzi, L., Lewington, C., Mudali, S., Kerrien, S., Orchard, S., Vingron, M., Roechert, B., Roepstorff, P., Valencia, A., Margalit, H., Armstrong, J., Bairoch, A., Cesareni, G., Sherman, D. & Apweller, R. (2004). IntAct: an open source molecular interaction database. Nucleic Acids Research 32, D452–D455.CrossRefGoogle ScholarPubMed
Higueruelo, A.P., Schreyer, A., Bickerton, G.R., Pitt, W.R., Groom, C.R. & Blundell, T.L. (2009). Atomic interactions and profile of small molecules disrupting protein–protein interfaces: the TIMBAL database. Chemistry Biology and Drug Design 74, 457–467.CrossRefGoogle ScholarPubMed
Hirai, H., Sootome, H., Nakatsuru, Y., Miyama, K., Taguchi, S., Tsujioka, K., Ueno, Y., Hatch, H., Majumder, P.K., Pan, B.S. & Kotani, H. (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, 1956–1967.CrossRefGoogle ScholarPubMed
Holdgate, G.A. & Ward, W.H. (2005). Measurements of binding thermodynamics in drug discovery. Drug Discovery Today 10, 1543–1550.CrossRefGoogle ScholarPubMed
Homans, S.W. (2004). NMR spectroscopy tools for structure-aided drug design. Angewandte Chemie International Edition 43, 290–300.CrossRefGoogle ScholarPubMed
Hopkins, A.L. & Groom, C.R. (2002). The druggable genome. Nature Reviews Drug Discovery 1, 727–730.CrossRefGoogle ScholarPubMed
Hopkins, A.L., Groom, C.R. & Alex, A. (2004). Ligand efficiency: a useful metric for lead selection. Drug Discovery Today 9, 430–431.CrossRefGoogle ScholarPubMed
Howard, N., Abell, C., Blakemore, W., Chessari, G., Congreve, M., Howard, S., Jhoti, H., Murray, C.W., Seavers, L.C. & Van Montfort, R.L. (2006). Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors. Journal of Medical Chemistry 49, 1346–1355.CrossRefGoogle Scholar
Hubbard, R.E., Davis, B., Chen, I. & Drysdale, M.J. (2007). The SeeDs approach: integrating fragments into drug discovery. Current Topics in Medicinal Chemistry 7, 1568–1581.CrossRefGoogle ScholarPubMed
Hubbard, R.E. & Murray, J.B. (2011). Experiences in fragment-based lead discovery. Methods in Enzymology 493, 509–531.CrossRefGoogle ScholarPubMed
Hung, A.W., Ramek, A., Wang, Y., Kaya, T., Wilson, J.A., Clemons, P.A. & Young, D.W. (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, 6799–6804.CrossRefGoogle Scholar
Hung, A.W., Silvestre, H.L., Wen, S., Ciulli, A., Blundell, T.L. & Abell, C. (2009). Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase. Angewandte Chemie International Edition 48, 8452–8456.CrossRefGoogle Scholar
Irwin, J.J. & Shoichet, B.K. (2005). ZINC – a free database of commercially available compounds for virtual screening. Journal of Chemical Information Model 45, 177–182.CrossRefGoogle ScholarPubMed
Jefferson, E.R., Walsh, T.P., Roberts, T.J. & Barton, G.J. (2007). SNAPPI-DB: a database and API of structures, iNterfaces and alignments for protein–protein interactions. Nucleic Acids Research 35 (Database issue), D580–D589.CrossRefGoogle ScholarPubMed
Jennings, L.D., Foreman, K.W., Rush, T.S. III, Tsao, D.H., Mosyak, L., Kincaid, S.L., Sukhdeo, M.N., Sutherland, A.G., Ding, W., Kenny, C.H., Sabus, C.L., Liu, H., Dushin, E.G., Moghazeh, S.L., Labthavikul, P., Petersen, P.J., Tuckman, M., Haney, S.A. & Ruzin, A.V. (2004a). Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of ZipA–FtsZ interaction. Bioorganic and Medicinal Chemistry 12, 5115–5131.CrossRefGoogle ScholarPubMed
Jennings, L.D., Foreman, K.W., Rush, T.S. III, Tsao, D.H., Mosyak, L., Li, Y., Sukhdeo, M.N., Ding, W., Dushin, E.G., Kenny, C.H., Moghazeh, S.L., Petersen, P.J., Ruzin, A.V., Tuckman, M. & Sutherland, A.G. (2004b). Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the ZipA–FtsZ interaction. Bioorganic and Medicinal Chemistry Lett 14, 1427–1431.CrossRefGoogle ScholarPubMed
Jochim, A.L. & Arora, P.S. (2009). Assessment of helical interfaces in protein–protein interactions. Molecular Biosystems 5, 924–926.CrossRefGoogle ScholarPubMed
Jochim, A.L. & Arora, P.S. (2010). Systematic analysis of helical protein interfaces reveals targets for synthetic inhibitors. ACS Chemical Biology 5, 919–923.CrossRefGoogle ScholarPubMed
Jonsson, U., Fagerstam, L., Ivarsson, B., Johnsson, B., Karlsson, R., Lundh, K., Lofas, S., Persson, B., Roos, H., Ronnberg, I. et al. (1991). Real-time biospecific interaction analysis using surface plasmon resonance and a sensor chip technology. Biotechniques 11, 620–627.Google Scholar
Jubb, H., Higueruelo, A., Winter, A. & Blundell, T. (2012). Structural biology and drug discovery for protein–protein interactions. Trends in Pharmacological Sciences 33, 241–248.CrossRefGoogle ScholarPubMed
Kalidas, Y. & Chandra, N. (2008). PocketDepth: a new depth based algorithm for identification of ligand binding sites in proteins. Journal of Structurall Biology 161, 31–42.CrossRefGoogle ScholarPubMed
Kenny, C.H., Ding, W., Kelleher, K., Benard, S., Dushin, E.G., Sutherland, A.G., Mosyak, L., Kriz, R. & Ellestad, G. (2003). Development of a fluorescence polarization assay to screen for inhibitors of the FtsZ/ZipA interaction. Analytical Biochemistry 323, 224–233.CrossRefGoogle ScholarPubMed
Keseru, G.M. & Makara, G.M. (2009). The influence of lead discovery strategies on the properties of drug candidates. Nature Reviews. Drug Discovery 8, 203–212.CrossRefGoogle ScholarPubMed
Keskin, O., Ma, B., Rogale, K., Gunasekaran, K. & Nussinov, R. (2005). Protein-protein interactions: organization, cooperativity and mapping in a bottom-up systems biology approach. Physical Biology 2, S24–35.CrossRefGoogle Scholar
Khurana, T.S. & Davies, K.E. (2003). Pharmacological strategies for muscular dystrophy. Nature Reviews Drug Discovery 2, 379–390.CrossRefGoogle ScholarPubMed
Kim, O., Jeong, Y., Lee, H., Hong, S.S. & Hong, S. (2011). Design and synthesis of imidazopyridine analogues as inhibitors of phosphoinositide 3-kinase signaling and angiogenesis. Journal of Medical Chemistry 54, 2455–2466.CrossRefGoogle ScholarPubMed
Kobayashi, M., Retra, K., Figaroa, F., Hollander, J.G., Ab, E., Heetebrij, R.J., Irth, H. & Siegal, G. (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, 978–989.CrossRefGoogle ScholarPubMed
Kortemme, T. & Baker, D. (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, 14116–14121.CrossRefGoogle ScholarPubMed
Krissinel, E. & Henrick, K. (2007). Inference of macromolecular assemblies from crystalline state. Journal of Molecular Biology 372, 774–797.CrossRefGoogle ScholarPubMed
Kuntz, I.D., Chen, K., Sharp, K.A. & Kollman, P.A. (1999). The maximal affinity of ligands. Proceedings of the National Academy of Sciences of the United States of America 96, 9997–10002.CrossRefGoogle ScholarPubMed
Lage, K., Karlberg, E.O., Storling, Z.M., Olason, P.I., Pedersen, A.G., Rigina, O., Hinsby, A.M., Tumer, Z., Pociot, F., Tommerup, N., Moreau, Y. & Brunak, S. (2007). A human phenome–interactome network of protein complexes implicated in genetic disorders. Nature Biotechnology 25, 309–316.CrossRefGoogle ScholarPubMed
Lauri, G. & Bartlett, P.A. (1994). CAVEAT: a program to facilitate the design of organic molecules. Journal of Computer-Aided Molecular Design 8, 51–66.CrossRefGoogle ScholarPubMed
Laurie, A.T. & Jackson, R.M. (2005). Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites. Bioinformatics 21, 1908–1916.CrossRefGoogle ScholarPubMed
Lawrence, S.H., Ramirez, U.D., Tang, L., Fazliyez, F., Kundrat, L., Markham, G.D. & Jaffe, E.K. (2008). Shape shifting leads to small-molecule allosteric drug discovery. Chemistry & Biology 15, 586–596.CrossRefGoogle ScholarPubMed
Le Guilloux, V., Schmidtke, P. & Tuffery, P. (2009). Fpocket: an open source platform for ligand pocket detection. BMC Bioinformatics 10, 168.CrossRefGoogle ScholarPubMed
Leavitt, S. & Freire, E. (2001). Direct measurement of protein binding energetics by isothermal titration calorimetry. Current Opinion in Structural Biology 11, 560–566.CrossRefGoogle ScholarPubMed
Lee, G.M. & Craik, C.S. (2009). Trapping moving targets with small molecules. Science 324, 213–215.CrossRefGoogle ScholarPubMed
Lee, S., Brown, A., Pitt, W., Higueruelo, A., Gong, S., Bickerton, G., Schreyer, A., Tanramluk, D., Baylay, A. & Blundell, T. (2009). Structural interactomics: informatics approaches to aid the interpretation of genetic variation and the development of novel therapeutics. Molecular Biosystems. 5, 1456–1472.CrossRefGoogle ScholarPubMed
Lepre, C.A. (2011). Practical aspects of NMR-based fragment screening. Methods in Enzymology 493, 219–239.CrossRefGoogle ScholarPubMed
Lepre, C.A., Moore, J.M. & Peng, J.W. (2004). Theory and applications of NMR-based screening in pharmacautical research. Chemical Reviews 104, 3641–3675.CrossRefGoogle Scholar
Leung, S.M., Senisterra, G., Ritchie, K.P., Sadis, S.E., Lepock, J.R. & Hightower, L.E. (1996). Thermal activation of the bovine Hsc70 molecular chaperone at physiological temperatures: physical evidence of a molecular thermometer. Cell Stress Chaperones 1, 78–89.2.3.CO;2>CrossRefGoogle ScholarPubMed
Li, J. & Liu, Q. (2009). ‘Double water exclusion’: a hypothesis refining the O-ring theory for the hot spots at protein interfaces. Bioinformatics 25, 743–750.CrossRefGoogle ScholarPubMed
Liepinsh, E. & Otting, G. (1997). Organic solvents identify specific ligand binding sites on protein surfaces. Nature Biotechnology 15, 264–268.CrossRefGoogle ScholarPubMed
Lipinski, C.A., Lombardo, F., Dominy, B.W. & Feeney, P.J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 46, 3–26.CrossRefGoogle ScholarPubMed
Lise, S., Buchan, D., Pontil, M. & Jones, D.T. (2011). Predictions of hot spot residues at protein–protein interfaces using support vector machines. PLoS ONE 6, e16774.CrossRefGoogle ScholarPubMed
Liu, C.C. & Schultz, P.G. (2010). Adding new chemistries to the genetic code. Annual Review of Biochemistry, 79, 413–444.CrossRefGoogle ScholarPubMed
Liu, G., Huth, J.R., Olejniczak, E.T., Mendoza, R., Devries, P., Leitza, S., Reilly, E.B., Okasinski, G.F., Fesik, S.W. & Von Geldern, T.W. (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, 1202–1210.CrossRefGoogle ScholarPubMed
Lo, M.C., Aulabaugh, A., Jin, G., Cowling, R., Bard, J., Malamas, M. & Ellestad, G. (2004). Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery. Analytical Biochemistry 332, 153–159.CrossRefGoogle ScholarPubMed
Luo, Q., Pagel, P., Vilne, B. & Frishman, D. (2011). DIMA 3.0: domain interaction map. Nucleic Acids Research 39 (Database issue), D724–D729.CrossRefGoogle ScholarPubMed
Mattos, C. & Ringe, D. (1996). Locating and characterizing binding sites on proteins. Nature Biotechnology 14, 595–599.CrossRefGoogle ScholarPubMed
Mauser, H. & Guba, W. (2008). Recent developments in de novo design and scaffold hopping. Current Opinion in Drug Discovery and Development 11, 365–374.Google ScholarPubMed
Mayer, M. & Meyer, B. (1999). Characterization of ligand binding by saturation transfer difference NMR spectroscopy. Angewandte Chemie International Edition 38, 1784–1788.3.0.CO;2-Q>CrossRefGoogle ScholarPubMed
Meireles, L.M., Domling, A.S. & Camacho, C.J. (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), W407–W411.CrossRefGoogle ScholarPubMed
Meyer, B. & Peters, T. (2003). NMR spectroscopy techniques for screening and identifying ligand binding to protein receptors. Angewandte Chemie International Edition 42, 864–890.CrossRefGoogle ScholarPubMed
Moellering, R.E., Cornejo, M., Davis, T.N., Del Bianco, C., Aster, J.C., Blacklow, S.C., Kung, A.L., Gilliland, D.G., Verdine, G.L. & Bradner, J.E. (2009). Direct inhibition of the NOTCH transcription factor complex. Nature 462, 182–188.CrossRefGoogle ScholarPubMed
Morita, M., Nakamura, S. & Shimizu, K. (2008). Highly accurate method for ligand-binding site prediction in unbound state (apo) protein structures. Proteins 73, 468–479.CrossRefGoogle ScholarPubMed
Muchmore, S.W., Olson, J., Jones, R., Pan, J., Blum, M., Greer, J., Merrick, S.M., Magdalinos, P. & Nienaber, V.L. (2000). Automated crystal mounting and data collection for protein crystallography. Structure 8, R243–R246.CrossRefGoogle ScholarPubMed
Murray, C.W. & Blundell, T.L. (2010). Structural biology in fragment-based drug design. Current Opinion in Structural Biology 20, 497–507.CrossRefGoogle ScholarPubMed
Navratilova, I., Besnard, J. & Hopkins, A.L. (2011). Screening for GPCR ligands using surface plasmon resonance. ACS Medicinal Chemistry Letters 2, 549–554.CrossRefGoogle ScholarPubMed
Navratilova, I. & Myszka, D. (2006). Investigating Biomolecular Interactions and Binding Properties using SPR Biosensors. New York: Springer.CrossRefGoogle Scholar
Nienaber, V.L., Richardson, P.L., Klighofer, V., Bouska, J.J., Giranda, V.L. & Greer, J. (2000). Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nature Biotechnology 18, 1105–1108.CrossRefGoogle ScholarPubMed
Nooren, I.M. & Thornton, J.M. (2003). Structural characterisation and functional significance of transient protein–protein interactions. Journal of Molecular Biology 325, 991–1018.CrossRefGoogle ScholarPubMed
Nordin, H., Jungnelius, M., Karlsson, R. & Karlsson, O.P. (2005). Kinetic studies of small molecule interactions with protein kinases using biosensor technology. Analytical Biochemistry 340, 359–368.CrossRefGoogle ScholarPubMed
Ogmen, U., Keskin, O., Aytuna, A.S., Nussinov, R. & Gursoy, A. (2005). PRISM: protein interactions by structural matching. Nucleic Acids Research 33 (Web Server issue), W331–W336.CrossRefGoogle ScholarPubMed
Olsson, T.S., Williams, M.A., Pitt, W.R. & Ladbury, J.E. (2008). The thermodynamics of protein–ligand interaction and solvation: insights for ligand design. Journal of Molecular Biology 384, 1002–1017.CrossRefGoogle ScholarPubMed
Oltersdorf, T., Elmore, S.W., Shoemaker, A.R., Armstrong, R.C., Augeri, D.J., Belli, B.A., Bruncko, M., Deckwerth, T.L., Dinges, J., Hajduk, P.J., Joseph, M.K., Kitada, S., Korsmeyer, S.J., Kunzer, A.R., Letai, A., Li, C., Mitten, M.J., Nettesheim, D.G., Ng, S., Nimmer, P.M., O'CONNOR, J.M., Oleksijew, A., Petros, A.M., Reed, J.C., Shen, W., Tahir, S.K., Thompson, C.B., Tomaselli, K.J., Wang, B., Wendt, M.D., Zhang, H., Fesik, S.W. & Rosenberg, S.H. (2005). An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681.CrossRefGoogle ScholarPubMed
Orchard, S., Kerrien, S., Jones, P., Ceol, A., Chatr-Aryamontri, A., Salwinski, L., Nerothin, J. & Hermjakob, H. (2007). Submit your interaction data the IMEx way: a step by step guide to trouble-free deposition. Proteomics 7 (Suppl. 1), 28–34.CrossRefGoogle Scholar
Pantolino, M.W., Petrella, E.C., Kwasnoski, J.D., Lobanov, V.S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B.A., Lane, P. & Salemme, F.R. (2001). High-density miniaturized thermal shift assays as a general strategy for drug discovery. Journal of Biomolecular Screening 6, 429–440.CrossRefGoogle Scholar
Pellegrini, L., Yu, D.S., Lo, T., Anand, S., Lee, M., Blundell, T.L. & Venkitaraman, A.R. (2002). Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature 420, 287–293.CrossRefGoogle ScholarPubMed
Perot, S., Sperandio, O., Miteva, M.A., Camproux, A.C. & Villoutreix, B.O. (2010). Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery. Drug Discovery Today 15, 656–667.CrossRefGoogle ScholarPubMed
Perspicace, S., Banner, D., Benz, J., Muller, F., Schlatter, D. & Huber, W. (2009). Fragment-based screening using surface plasmon resonance technology. Journal of Biomolecular Screening: The Official Journal of the Society for Biomolecular Screening 14, 337–349.CrossRefGoogle ScholarPubMed
Petros, A.M., Dinges, J., Augeri, D.J., Baumeister, S.A., Betebenner, D.A., Bures, M.G., Elmore, S.W., Hajduk, P.J., Joseph, M.K., Landis, S.K., Nettesheim, D.G., Rosenberg, S.H., Shen, W., Thomas, S., Wang, X., Zanze, I., Zhang, H. & Fesik, S.W. (2006). Discovery of a potent inhibitor of the antiapoptotic protein Bcl-XL from NMR and parallel synthesis. Journal of Medicinal Chemistry 49, 656–663.CrossRefGoogle ScholarPubMed
Pierce, M.M., Raman, C.S. & Nall, B.T. (1999). Isothermal titration calorimetry of protein–protein interactions. Methods 19, 213–221.CrossRefGoogle ScholarPubMed
Pitt, W., Higueruelo, A. & Todorov, N. (2010). Fragment-based methods for lead discovery. In In Silico Lead Discovery (ed. Miteva, M.), pp. 83–116. Paris: Bentham Science Publishers.Google Scholar
Rajamani, D., Thiel, S., Vajda, S. & Camacho, C.J. (2004). Anchor residues in protein–protein interactions. Proceedings of the National Academy of Sciences of the United States of America 101, 11287–11292.CrossRefGoogle ScholarPubMed
Razavi, H., Palaninathan, S.K., Powers, E.T., Wiseman, R.L., Purkey, H.E., Mohamedmohaideen, N.N., Deechongkit, S., Chiang, K.P., Dendle, M.T., Sacchettini, J.C. & Kelly, J.W. (2003). Benzoxazoles as transthyretin amyloid fibril inhibitors: synthesis, evaluation, and mechanism of action. Angewandte Chemie International Edition 42, 2758–2761.CrossRefGoogle ScholarPubMed
Rohrig, C.H., Loch, C., Guan, J.Y., Siegal, G. & Overhand, M. (2007). Fragment-based synthesis and SAR of modified FKBP ligands: influence of different linking on binding affinity. Chem Med Chem 2, 1054–1070.CrossRefGoogle ScholarPubMed
Rush, T.S. 3rd, Grant, J.A., Mosyak, L. & Nicholls, A. (2005). A shape-based 3-D scaffold hopping method and its application to a bacterial protein–protein interaction. Journal of Medical Chemistry 48, 1489–1495.CrossRefGoogle ScholarPubMed
Sasaki, K., Dockerill, S., Adamiak, D.A., Tickle, I.J. & Blundell, T. (1975). X-ray analysis of glucagon and its relationship to receptor binding. Nature 257, 751–757.CrossRefGoogle ScholarPubMed
Saxty, G., Woodhead, S.J., Berdini, V., Davies, T.G., Verdonk, M.L., Wyatt, P.G., Boyle, R.G., Barford, D., Downham, R., Garrett, M.D. & Carr, R.A. (2007). Identification of inhibitors of protein kinase B using fragment-based lead discovery. Journal of Medical Chemistry 50, 2293–2296.CrossRefGoogle ScholarPubMed
Schmidtke, P. & Barril, X. (2010). Understanding and predicting druggability. A high-throughput method for detection of drug binding sites. Journal of Medical Chemistry 53, 5858–5867.CrossRefGoogle ScholarPubMed
Schmidtke, P., Souaille, C., Estienne, F., Baurin, N. & Kroemer, R.T. (2010). Large-scale comparison of four binding site detection algorithms. Journal of Chemical Information Model 50, 2191–2200.CrossRefGoogle ScholarPubMed
Schneider, G. & Fechner, U. (2005). Computer-based de novo design of drug-like molecules. Nature Reviews Drug Discovery 4, 649–663.CrossRefGoogle ScholarPubMed
Schwyzer, R., Kriwaczek, V.M., Baumann, K., Haller, H.-R., Wider, G. & Wiltzius, A.P. (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, 831–835.CrossRefGoogle Scholar
Scott, D.E., Ehebauer, M.T., Pukala, T., Marsh, M., Blundell, T.L., Venkitaraman, A.R., Abell, C. & Hyvönen, M. (2012). Using a fragment-based approach to target protein–protein interactions. Manuscript in Preparation.Google Scholar
Segura, J. & Fernandez-Fuentes, N. (2011). PCRPi-DB: a database of computationally annotated hot spots in protein interfaces. Nucleic Acids Research 39 (Database issue), D755–D760.CrossRefGoogle ScholarPubMed
Shuker, S.B., Hajduk, P.J., Meadows, R.P. & Fesik, S.W. (1996). Discovering high-affinity ligands for proteins: SAR by NMR. Science 274, 1531–1534.CrossRefGoogle ScholarPubMed
Sigurdardottir, A. (2012). Targeting hepatocyte growth factor/scatter factor for drug discovery using a fragment-based approach. PhD thesis, University of Cambridge.Google Scholar
Sigurskjold, B.W. (2000). Exact analysis of competition ligand binding by displacement isothermal titration calorimetry. Analytical Biochemistry 277, 260–266.CrossRefGoogle ScholarPubMed
Sledz, P., Zheng, H., Murzyn, K., Chruszcz, M., Zimmerman, M.D., Chordia, M.D., Joachimiak, A. & Minor, W. (2010). New surface contacts formed upon reductive lysine methylation: improving the probability of protein crystallization. Protein Science: A Publication of the Protein Society 19, 1395–1404.CrossRefGoogle ScholarPubMed
Smialowski, P., Pagel, P., Wong, P., Brauner, B., Dunger, I., Fobo, G., Frishman, G., Montrone, C., Rattei, T., Frishman, D. & Ruepp, A. (2010). The Negatome database: a reference set of non-interacting protein pairs. Nucleic Acids Research 38 (Database issue), D540–D544.CrossRefGoogle ScholarPubMed
Spurlino, J.C. (2011). Fragment screening purely with protein crystallography. Methods in Enzymology 493, 321–356.CrossRefGoogle ScholarPubMed
Stein, A., Ceol, A. & Aloy, P. (2011). 3did: identification and classification of domain-based interactions of known three-dimensional structure. Nucleic Acids Research 39 (Database issue), D718–D723.CrossRefGoogle ScholarPubMed
Stewart, M.L., Fire, E., Keating, A.E. & Walensky, L.D. (2010). The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nature Chemical Biology 6, 595–601.CrossRefGoogle ScholarPubMed
Stockman, B.J., Kothe, M., Kohls, D., Weibley, L., Connolly, B.J., Sheils, A.L., Cao, Q., Cheng, A.C., Yang, L., Kamath, A.V., Ding, Y.H. & Charlton, M.E. (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, 179–188.CrossRefGoogle ScholarPubMed
Sugase, K., Dyson, H.J. & Wright, P.E. (2007). Mechanism of coupled folding and binding of an intrinsically disordered protein. Nature 447, 1021–1025.CrossRefGoogle ScholarPubMed
Sugaya, N. & Furuya, T. (2011). Dr. PIAS: an integrative system for assessing the druggability of protein–protein interactions. BMC Bioinformatics 12, 50.CrossRefGoogle ScholarPubMed
Sugaya, N. & Ikeda, K. (2009). Assessing the druggability of protein–protein interactions by a supervised machine-learning method. BMC Bioinformatics 10, 263.CrossRefGoogle ScholarPubMed
Sutherland, A.G., Alvarez, J., Ding, W., Foreman, K.W., Kenny, C.H., Labthavikul, P., Mosyak, L., Petersen, P.J., Rush, T.S. 3rd, Ruzin, A., Tsao, D.H. & Wheless, K.L. (2003). Structure-based design of carboxybiphenylindole inhibitors of the ZipA–FtsZ interaction. Organic and Biomolecular Chemistry 1, 4138–4140.CrossRefGoogle ScholarPubMed
Szklarczyk, D., Franceschini, A., Kuhn, M., Simonovic, M., Roth, A., Minguez, P., Doerks, T., Stark, M., Muller, J., Bork, P., Jensen, L.J. & Von Mering, C. (2011). The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Research 39 (Database issue), D561–D568.CrossRefGoogle ScholarPubMed
Taylor, J.D., Gilbert, P.J., Williams, M.A., Pitt, W.R. & Ladbury, J.E. (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, 981–990.CrossRefGoogle ScholarPubMed
Teyra, J., Paszkowski-Rogacz, M., Anders, G. & Pisabarro, M.T. (2008). SCOWLP classification: structural comparison and analysis of protein binding regions. BMC Bioinformatics 9, 9.CrossRefGoogle ScholarPubMed
Thanos, C.D., Delano, W.L. & Wells, J.A. (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, 15422–15427.CrossRefGoogle ScholarPubMed
Thompson, D., Denny, A., Nilakantan, R., Humblet, C., Joseph-Mccarthy, D. & Feyfant, E. (2008). CONFIRM: connecting fragments found in receptor molecules. Journal of Computer-Aided Molecular Design 22, 761–772.CrossRefGoogle ScholarPubMed
Thorn, K.S. & Bogan, A.A. (2001). ASEdb: a database of alanine mutations and their effects on the free energy of binding in protein interactions. Bioinformatics 17, 284–285.CrossRefGoogle ScholarPubMed
Tilley, J.W., Chen, L., Fry, D.C., Emerson, S.D., Powers, G.D., Biondi, D., Varnell, T., Trilles, R., Guthrie, R., Mennona, F., Kaplan, G., Lemahieu, R.A., Carson, M., Han, R.-J., Liu, C.-M., Palermo, R. & Ju, G. (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, 7589–7590.CrossRefGoogle Scholar
Tolcher, A., Yap, T., Fearen, I., Taylor, A., Carpenter, C. & Brunetto, A. (2007). A phase I study of MK-2206, an oral potent allosteric Akt inhibitor, in patients with advanced solid tumor. Journal of Clinical Oncology 27, 3503.CrossRefGoogle Scholar
Torres, F.E., Recht, M.I., Coyle, J.E., Bruce, R.H. & Williams, G. (2010). Higher throughput calorimetry: opportunities, approaches and challenges. Current Opinion in Structural Biology 20, 598–605.CrossRefGoogle ScholarPubMed
Traczewski, P. & Rudnicka, L. (2011). Treatment of systemic lupus erythematosus with epratuzumab. British Journal of Clinical Pharmacology 71, 175–182.CrossRefGoogle ScholarPubMed
Tsao, D.H., Sutherland, A.G., Jennings, L.D., Li, Y., Rush, T.S. III, Alvarez, J.C., Ding, W., Dushin, E.G., Dushin, R.G., Haney, S.A., Kenny, C.H., Malakian, A.K., Nilakantan, R. & Mosyak, L. (2006). Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design. Bioorganic and Medicinal Chemistry 14, 7953–7961.CrossRefGoogle ScholarPubMed
Tuncbag, N., Kar, G., Keskin, O., Gursoy, A. & Nussinov, R. (2009). A survey of available tools and web servers for analysis of protein–protein interactions and interfaces. Briefings in Bioinformatics 10, 217–232.CrossRefGoogle ScholarPubMed
Turinsky, A.L., Razick, S., Turner, B., Donaldson, I.M. & Wodak, S.J. (2011). Interaction databases on the same page. Nature Biotechnology 29, 391–393.CrossRefGoogle ScholarPubMed
Turnbull, W.B. & Daranas, A.H. (2003). On the value of c: can low affinity systems be studied by isothermal titration calorimetry? Journal of the American Chemical Society 125, 14859–14866.CrossRefGoogle ScholarPubMed
Tversky, A. (1977). Features of Similarity. Psychological Reviews 84, 327–352.CrossRefGoogle Scholar
Vedadi, M., Niesen, F.H., Allali-Hassani, A., Fedorov, O.Y., Finerty, P.J. Jr., Wasney, G.A., Yeung, R., Arrowsmith, C., Ball, L.J., Berglund, H., Hui, R. & Marsden, B.D. (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, 15835–15840.CrossRefGoogle ScholarPubMed
Velazquez-Campoy, A., Kiso, Y. & Freire, E. (2001). The binding energetics of first- and second-generation HIV-1 protease inhibitors: implications for drug design. Archives of Biochemistry and Biophysics 390, 169–175.CrossRefGoogle ScholarPubMed
Velazquez-Campoy, A., Todd, M.J. & Freire, E. (2000). HIV-1 protease inhibitors: enthalpic versus entropic optimization of the binding affinity. Biochemistry 39, 2201–2207.CrossRefGoogle ScholarPubMed
Venkatesan, K., Rual, J.F., Vazquez, A., Stelzl, U., Lemmens, I., Hirozane-Kishikawa, T., Hao, T., Zenkner, M., Xin, X., Goh, K.I., Yildirim, M.A., Simonis, N., Heinzmann, K., Gebreab, F., Sahalie, J.M., Cevik, S., Simon, C., De Smet, A.S., Dann, E., Smolyar, A., Vinayagam, A., Yu, H., Szeto, D., Borick, H., Dricot, A., Klitgord, N., Murray, R.R., Lin, C., Lalowski, M., Timm, J., Rau, K., Boone, C., Braun, P., Cusick, M.E., Roth, F.P., Hill, D.E., Tavernier, J., Wanker, E.E., Barabasi, A.L. & Vidal, M. (2009). An empirical framework for binary interactome mapping. Nature Methods 6, 83–90.CrossRefGoogle ScholarPubMed
Verlinde, C.L.M. J., Kim, H.B.B., Mande, S.C. & Wgj, H. (1997). Anti-trypanosomiasis Drug Development Based on Structures of Glycolytic Enzymes. New York: Marcel Dekker; Inc.Google Scholar
Vinkers, H.M., De Jonge, M.R., Daeyaert, F.F.D., Heeres, J., Koymans, L.M.H., Van Lenthe, J.H., Lewi, P.J., Timmerman, H., Van Aken, K. & Janssen, P.A.J. (2003). SYNOPSIS: SYNthesize and OPtimize System in Silico. Journal of Medicinal Chemistry 46, 2765–2773.CrossRefGoogle ScholarPubMed
Waldron, T.T. & Murphy, K.P. (2003). Stabilization of proteins by ligand binding: application to drug screening and determination of unfolding energetics. Biochemistry 42, 5058–5064.CrossRefGoogle ScholarPubMed
Wang, L. & Schultz, P.G. (2004). Expanding the genetic code. Angewandte Chemie International Edition 44, 34–66.CrossRefGoogle ScholarPubMed
Wang, Z.X. (1995). An exact mathematical expression for describing competitive binding of two different ligands to a protein molecule. FEBS Letters 360, 111–114.CrossRefGoogle ScholarPubMed
Wells, J. & Mcclendon, C. (2007). Reaching for high-hanging fruit in drug discovery at protein–protein interfaces. Nature 450, 1001–1009.CrossRefGoogle ScholarPubMed
Wendt, M.D., Sun, C., Kunzer, A., Sauer, D., Sarris, K., Hoff, E., Yu, L., Nettesheim, D.G., Chen, J., Jin, S., Comess, K.M., Fan, Y., Anderson, S.N., Isaac, B., Olejniczak, E.T., Hajduk, P.J., Rosenberg, S.H. & Elmore, S.W. (2007). Discovery of a novel small molecule binding site of human survivin. Bioorganic and Medicinal Chemistry Lett 17, 3122–3129.CrossRefGoogle ScholarPubMed
Wilson, A.J. (2009). Inhibition of protein–protein interactions using designed molecules. Chemical Society Reviews 38, 3289–3300.CrossRefGoogle ScholarPubMed
Winter, C., Henschel, A., Kim, W.K. & Schroeder, M. (2006). SCOPPI: a structural classification of protein–protein interfaces. Nucleic Acids Research 34(Database issue), D310–D314.CrossRefGoogle ScholarPubMed
Wiseman, T., Williston, S., Brandts, J.F. & Lin, L.N. (1989). Rapid measurement of binding constants and heats of binding using a new titration calorimeter. Analytical Biochemistry 179, 131–137.CrossRefGoogle ScholarPubMed
Wright, P.E. & Dyson, H.J. (1999). Intrinsically unstructured proteins: re-assessing the protein structure–function paradigm. Journal of Molecular Biology 293, 321–331.CrossRefGoogle ScholarPubMed
Wright, P.E. & Dyson, H.J. (2009). Linking folding and binding. Current Opinion in Structural Biology 19, 31–38.CrossRefGoogle ScholarPubMed
Wu, W.I., Voegtli, W.C., Sturgis, H.L., Dizon, F.P., Vigers, G.P. & Brandhuber, B.J. (2010). Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. PLoS ONE 5, e12913.CrossRefGoogle ScholarPubMed
Xenarios, I., Rice, D.W., Salwinski, L., Baron, M.K., Marcotte, E.M. & Eisenberg, D. (2000). DIP: the database of interacting proteins. Nucleic Acids Research 28, 289–291.CrossRefGoogle ScholarPubMed
Xiang, Y., Hirth, B., Asmussen, G., Biemann, H.P., Bishop, K.A., Good, A., Fitzgerald, M., Gladysheva, T., Jain, A., Jancsics, K., Liu, J., Metz, M., Papoulis, A., Skerlj, R., Stepp, J.D. & Wei, R.R. (2011). The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors. Bioorganic and Medicinal Chemistry Lett 21, 3050–3056.CrossRefGoogle ScholarPubMed
Xu, Q., Canutescu, A., Obradovic, Z. & Dunbrack, R.L. Jr., ( 2006). ProtBuD: a database of biological unit structures of protein families and superfamilies. Bioinformatics 22, 2876–2882.CrossRefGoogle ScholarPubMed
Yellaboina, S., Tasneem, A., Zaykin, D.V., Raghavachari, B. & Jothi, R. (2011). DOMINE: a comprehensive collection of known and predicted domain–domain interactions. Nucleic Acids Research 39(Database issue), D730–D735.CrossRefGoogle Scholar
Yin, H. & Hamilton, A.D. (2004). Terephthalamide derivatives as mimetics of the helical region of Bak peptide target Bcl-XL protein. Bioorganic and Medicinal Chemistry Lett 14, 1375–1379.CrossRefGoogle ScholarPubMed
Young, A.B. (2003). Huntingtin in health and disease. Journal of Clinical Investigation 111, 299–302.CrossRefGoogle ScholarPubMed
Young, T.S. & Schultz, P.G. (2010). Beyond the canonical 20 amino acids: expanding the genetic lexicon. The Journal of Biological Chemistry 285, 11039–11044.CrossRefGoogle ScholarPubMed