Fragment-based drug discovery (FBDD) is playing an increasingly important part in delivering candidates to the clinic.
Compared with screens of lead- or drug-sized molecules, fragments allow for a more thorough search of chemical space and can lead to superior molecules.
Fragments can provide fundamental insights into molecular recognition between proteins and ligands.
Rigorous use of multiple biophysical techniques is essential to identify and validate fragments.
Early and creative medicinal chemistry is needed to transform a low-affinity fragment into a lead molecule.
FBDD can be integrated with other lead discovery methods to tackle difficult problems.
After 20 years of sometimes quiet growth, fragment-based drug discovery (FBDD) has become mainstream. More than 30 drug candidates derived from fragments have entered the clinic, with two approved and several more in advanced trials. FBDD has been widely applied in both academia and industry, as evidenced by the large number of papers from universities, non-profit research institutions, biotechnology companies and pharmaceutical companies. Moreover, FBDD draws on a diverse range of disciplines, from biochemistry and biophysics to computational and medicinal chemistry. As the promise of FBDD strategies becomes increasingly realized, now is an opportune time to draw lessons and point the way to the future. This Review briefly discusses how to design fragment libraries, how to select screening techniques and how to make the most of information gleaned from them. It also shows how concepts from FBDD have permeated and enhanced drug discovery efforts.
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Macarron, R. et al. Impact of high-throughput screening in biomedical research. Nat. Rev. Drug Discov. 10, 188–195 (2011).
Barker, A., Kettle, J. G., Nowak, T. & Pease, J. E. Expanding medicinal chemistry space. Drug Discov. Today 18, 298–304 (2013).
McGovern, S. L., Caselli, E., Grigorieff, N. & Shoichet, B. K. A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. J. Med. Chem. 45, 1712–1722 (2002).
Irwin, J. J. et al. An aggregation advisor for ligand discovery. J. Med. Chem. 58, 7076–7087 (2015).
Bohacek, R. S., McMartin, C. & Guida, W. C. The art and practice of structure-based drug design: a molecular modeling perspective. Med. Res. Rev. 16, 3–50 (1996).
Ruddigkeit, L., van Deursen, R., Blum, L. C. & Reymond, J. L. Enumeration of 166 billion organic small molecules in the chemical universe database GDB-17. J. Chem. Inform. Mod. 52, 2864–2875 (2012).
Doak, B. C., Morton, C. J., Simpson, J. S. & Scanlon, M. J. Design and evaluation of the performance of an NMR screening fragment library. Aus. J. Chem. 66, 1465–1472 (2013).
Ferenczy, G. G. & Keseru, G. M. How are fragments optimized? A retrospective analysis of 145 fragment optimizations. J. Med. Chem. 56, 2478–2486 (2013).
Hann, M. M., Leach, A. R. & Harper, G. Molecular complexity and its impact on the probability of finding leads for drug discovery. J. Chem. Inf. Comput. Sci. 41, 856–864 (2001).
Leach, A. R. & Hann, M. M. Molecular complexity and fragment-based drug discovery: ten years on. Curr. Opin. Chem. Biol. 15, 489–496 (2011). References 9 and 10 discuss the concept of molecular complexity, which is part of the theoretical framework underlying FBDD.
Hann, M. M. Molecular obesity, potency and other addictions in drug discovery. Med. Chem. Commun. 2, 349–255 (2011).
Leeson, P. D. & St-Gallay, S. A. The influence of the 'organizational factor' on compound quality in drug discovery. Nat. Rev. Drug Discov. 10, 749–765 (2011).
Young, R. J. in Tactics in Contemporary Drug Design. Vol. 9 (ed. Meanwell, N. A.) 1–68 (Springer-Verlag Berlin Heidelberg, 2014).
Jencks, W. P. On the attribution and additivity of binding energies. Proc. Nat. Acad. Sci. USA 78, 4046–4050 (1981). This paper is often considered to mark the theoretical origin of FBDD.
Shuker, S. B., Hajduk, P. J., Meadows, R. P. & Fesik, S. W. Discovering high-affinity ligands for proteins: SAR by NMR. Science 274, 1531–1534 (1996). This paper, arguably the first practical demonstration of FBDD, is widely viewed as having jump-started the field.
Hajduk, P. J. et al. Discovery of potent nonpeptide inhibitors of stromelysin using SAR by NMR. J. Am. Chem. Soc. 119, 5818–5827 (1997).
Erlanson, D. A. & Jahnke, W. (eds) Fragment-based Drug Discovery: Lessons and Outlook. Vol. 67 (Wiley-VCH, 2016). This book is the most recent of 8 books devoted to FBDD, and its 19 chapters cover all aspects of the field.
Harner, M. J., Frank, A. O. & Fesik, S. W. Fragment-based drug discovery using NMR spectroscopy. J. Biol. NMR 56, 65–75 (2013).
Wang, F. & Fesik, S. W. in Fragment-based Drug Discovery: Lessons and Outlook. Vol. 67 (eds Erlanson, D. A. & Jahnke, W.) 371–390 (Wiley-VCH, 2016).
Keseru, G. M. et al. Design principles for fragment libraries: maximizing the value of learnings from Pharma fragment based drug discovery (FBDD) programs for use in academia. J. Med. Chem. http://dx.doi.org/10.1021/acs.jmedchem.6b00197 (2016).
Congreve, M., Carr, R., Murray, C. & Jhoti, H. A 'rule of three' for fragment-based lead discovery? Drug Discov. Today 8, 876–877 (2003).
Jhoti, H., Williams, G., Rees, D. C. & Murray, C. W. The 'rule of three' for fragment-based drug discovery: where are we now? Nat. Rev. Drug Discov. 12, 644–645 (2013). This paper and reference 21establish practical and theoretical guidelines for defining fragments.
Hall, R. J., Mortenson, P. N. & Murray, C. W. Efficient exploration of chemical space by fragment-based screening. Prog. Biophys. Mol. Biol. 116, 82–91 (2014).
Hajduk, P. J., Bures, M., Praestgaard, J. & Fesik, S. W. Privileged molecules for protein binding identified from NMR-based screening. J. Med. Chem. 43, 3443–3447 (2000).
Hajduk, P. J. et al. NMR-based screening of proteins containing 13C-labeled methyl groups. J. Am. Chem. Soc. 122, 7898–7904 (2000).
Erlanson, D. A. in Fragment-based Drug Discovery. Vol. 47 (eds Howard, S. & Abell, C.) 19–30 (Royal Society of Chemistry, 2015).
Friberg, A. et al. Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design. J. Med. Chem. 56, 15–30 (2013).
Davis, B. J. & Erlanson, D. A. Learning from our mistakes: the 'unknown knowns' in fragment screening. Bioorg. Med. Chem. Lett. 23, 2844–2852 (2013).
Dalvit, C., Caronni, D., Mongelli, N., Veronesi, M. & Vulpetti, A. NMR-based quality control approach for the identification of false positives and false negatives in high throughput screening. Curr. Drug Discov. Technol. 3, 115–124 (2006).
Huth, J. R. et al. ALARM NMR: a rapid and robust experimental method to detect reactive false positives in biochemical screens. J. Am. Chem. Soc. 127, 217–224 (2005).
Baell, J. B. & Holloway, G. A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem. 53, 2719–2740 (2010).
Baell, J. B. Observations on screening-based research and some concerning trends in the literature. Future Med. Chem. 2, 1529–1546 (2010).
Baell, J. & Walters, M. A. Chemistry: chemical con artists foil drug discovery. Nature 513, 481–483 (2014).
Seidler, J., McGovern, S. L., Doman, T. N. & Shoichet, B. K. Identification and prediction of promiscuous aggregating inhibitors among known drugs. J. Med. Chem. 46, 4477–4486 (2003).
Feng, B. Y., Shelat, A., Doman, T. N., Guy, R. K. & Shoichet, B. K. High-throughput assays for promiscuous inhibitors. Nat. Chem. Biol. 1, 146–148 (2005).
Morley, A. D. et al. Fragment-based hit identification: thinking in 3D. Drug Discov. Today 18, 1221–1227 (2013).
Davies, D. R. et al. Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography. J. Med. Chem. 52, 4694–4715 (2009).
Over, B. et al. Natural-product-derived fragments for fragment-based ligand discovery. Nat. Chem. 5, 21–28 (2013).
Vulpetti, A. & Dalvit, C. Design and generation of highly diverse fluorinated fragment libraries and their efficient screening with improved 19F NMR methodology. ChemMedChem. 8, 2057–2069 (2013).
Akritopoulou-Zanze, I. & Hajduk, P. J. Kinase-targeted libraries: the design and synthesis of novel, potent, and selective kinase inhibitors. Drug Discov. Today 14, 291–297 (2009).
Ostermann, N. et al. A novel class of oral direct renin inhibitors: highly potent 3,5-disubstituted piperidines bearing a tricyclic p3-p1 pharmacophore. J. Med. Chem. 56, 2196–2206 (2013).
Rüdisser, S., Vangrevelinghe, E. & Maibaum, J. in Fragment-based Drug Discovery: Lessons and Outlook. Vol. 67 (eds Erlanson, D. A. & Jahnke, W.) 447–486 (Wiley-VCH, 2016).
Lepre, C. A. Practical aspects of NMR-based fragment screening. Methods Enzymol. 493, 219–239 (2011).
Stockman, B. J. & Dalvit, C. NMR screening techniques in drug discovery and drug design. Prog. Nucl. Mag. Res. Spectrosc. 41, 183–231 (2002).
Cala, O. & Krimm, I. Ligand-orientation based fragment selection in STD NMR screening. J. Med. Chem. 58, 8739–8742 (2015).
Dalvit, C., Fagerness, P. E., Hadden, D. T., Sarver, R. W. & Stockman, B. J. Fluorine-NMR experiments for high-throughput screening: theoretical aspects, practical considerations, and range of applicability. J. Am. Chem. Soc. 125, 7696–7703 (2003).
Giannetti, A. M. From experimental design to validated hits a comprehensive walk-through of fragment lead identification using surface plasmon resonance. Methods Enzymol. 493, 169–218 (2011).
Danielson, U. H. Integrating surface plasmon resonance biosensor-based interaction kinetic analyses into the lead discovery and optimization process. Future Med. Chem. 1, 1399–1414 (2009).
Jhoti, H., Cleasby, A., Verdonk, M. & Williams, G. Fragment-based screening using X-ray crystallography and NMR spectroscopy. Curr. Opin. Chem. Biol. 11, 485–493 (2007).
Schiebel, J. et al. Six biophysical screening methods miss a large proportion of crystallographically discovered fragment hits: a case study. ACS Chem. Biol. 11, 1693–1701 (2016).
Davies, T. G. et al. Monoacidic inhibitors of the Kelch-like ECH-associated protein 1: nuclear factor erythroid 2–related factor 2 (KEAP1:NRF2) protein–protein interaction with high cell potency identified by fragment-based discovery. J. Med. Chem. 59, 3991–4006 (2016).
Hartshorn, M. J. et al. Fragment-based lead discovery using X-ray crystallography. J. Med. Chem. 48, 403–413 (2005).
Koh, C. Y. et al. A binding hotspot in Trypanosoma cruzi histidyl-tRNA synthetase revealed by fragment-based crystallographic cocktail screens. Acta Crystallogr. D Biol. Crystallogr. 71, 1684–1698 (2015).
Mashalidis, E. H., Sledz, P., Lang, S. & Abell, C. A three-stage biophysical screening cascade for fragment-based drug discovery. Nat. Prot. 8, 2309–2324 (2013).
Scott, D. E., Spry, C. & Abell, C. in Fragment-based drug discovery: Lessons and outlook (eds Erlanson, D. A. & Jahnke, W.) 139–172 (Wiley-VCH, 2016).
Jerabek-Willemsen, M., Wienken, C. J., Braun, D., Baaske, P. & Duhr, S. Molecular interaction studies using microscale thermophoresis. Assay Drug Dev. Technol. 9, 342–353 (2011).
Meiby, E. et al. Fragment screening by weak affinity chromatography: comparison with established techniques for screening against HSP90. Anal. Chem. 85, 6756–6766 (2013).
Wielens, J. et al. Parallel screening of low molecular weight fragment libraries: do differences in methodology affect hit identification? J. Biomol. Screen. 18, 147–159 (2013).
Schiebel, J. et al. One question, multiple answers: biochemical and biophysical screening methods retrieve deviating fragment hit lists. ChemMedChem. 10, 1511–1521 (2015).
Kutchukian, P. S. et al. Large scale meta-analysis of fragment-based screening campaigns: privileged fragments and complementary technologies. J. Biomol. Screen. 20, 588–596 (2015).
Ludlow, R. F., Verdonk, M. L., Saini, H. K., Tickle, I. J. & Jhoti, H. Detection of secondary binding sites in proteins using fragment screening. Proc. Nat. Acad. Sci. USA 112, 15910–15915 (2015).
Murray, C. W., Verdonk, M. L. & Rees, D. C. Experiences in fragment-based drug discovery. Trends Pharmacol. Sci. 33, 224–232 (2012).
Hopkins, A. L., Groom, C. R. & Alex, A. Ligand efficiency: a useful metric for lead selection. Drug Discov. Today 9, 430–431 (2004).
Hopkins, A. L., Keseru, G. M., Leeson, P. D., Rees, D. C. & Reynolds, C. H. The role of ligand efficiency metrics in drug discovery. Nat. Rev. Drug Discov. 13, 105–121 (2014). This review discusses the appropriate uses of various metrics such as ligand efficiency.
Bamborough, P., Brown, M. J., Christopher, J. A., Chung, C. W. & Mellor, G. W. Selectivity of kinase inhibitor fragments. J. Med. Chem. 54, 5131–5143 (2011).
Allen, C., Welford, A., Matthews, T., Caldwell, J. & Collins, I. Fragment growing to retain or alter the selectivity of anchored kinase hinge-binding fragments. Med. Chem. Commun. 5, 180–185 (2014).
Woolford, A. J. Experiences with fragment libraries at Astex. Presented at the Fragment-based Lead Discovery (FBLD) Conference. (2014).
Hubbard, R. E. in Fragment-based Drug Discovery: Lessons and Outlook. Vol. 67 (eds Erlanson, D. A. & Jahnke, W.) 3–36 (Wiley-VCH, 2016).
Devine, S. M. et al. Promiscuous 2-aminothiazoles (PrATs): a frequent hitting scaffold. J. Med. Chem. 58, 1205–1214 (2015).
Bauman, J. D., Harrison, J. J. & Arnold, E. Rapid experimental SAD phasing and hot-spot identification with halogenated fragments. IUCrJ 3, 51–60 (2016).
Bauman, J. D. et al. Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening. J. Med. Chem. 56, 2738–2746 (2013).
Kozakov, D. et al. Ligand deconstruction: why some fragment binding positions are conserved and others are not. Proc. Nat. Acad. Sci. USA 112, E2585–E2594 (2015).
Saalau-Bethell, S. M. et al. Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function. Nat. Chem. Biol. 8, 920–925 (2012).
Murray, J. et al. Tailoring small molecules for an allosteric site on procaspase-6. ChemMedChem. 9, 73–77 (2014).
Hajduk, P. J., Huth, J. R. & Fesik, S. W. Druggability indices for protein targets derived from NMR-based screening data. J. Med. Chem. 48, 2518–2525 (2005).
Chen, I. J. & Hubbard, R. E. Lessons for fragment library design: analysis of output from multiple screening campaigns. J. Comput. Aided Mol. Des. 23, 603–620 (2009).
Lau, W. F. et al. Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics. J. Comput. Aided Mol. Des. 25, 621–636 (2011).
Borsi, V., Calderone, V., Fragai, M., Luchinat, C. & Sarti, N. Entropic contribution to the linking coefficient in fragment based drug design: a case study. J. Med. Chem. 53, 4285–4289 (2010).
Ichihara, O., Barker, J., Law, R. J. & Whittaker, M. Compound design by fragment-linking. Mol. Informat. 30, 298–306 (2011).
Ward, R. A. et al. Design and synthesis of novel lactate dehydrogenase a inhibitors by fragment-based lead generation. J. Med. Chem. 55, 3285–3306 (2012).
Korczynska, M. et al. Docking and linking of fragments to discover jumonji histone demethylase inhibitors. J. Med. Chem. 59, 1580–1598 (2016).
Czaplewski, L. G. et al. Antibacterial alkoxybenzamide inhibitors of the essential bacterial cell division protein FtsZ. Bioorg. Med. Chem. Lett. 19, 524–527 (2009).
Murray, C. W. & Rees, D. C. Opportunity knocks: organic chemistry for fragment-based drug discovery (FBDD). Angew. Chem. Int. 55, 488–492 (2016).
Bollag, G. et al. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat. Rev. Drug Discov. 11, 873–886 (2012). This review discusses the discovery of the first approved FBDD-derived drug.
Addie, M. et al. Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3- d]pyrimidin -4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. J. Med. Chem. 56, 2059–2073 (2013).
Caldwell, J. J. et al. Identification of 4-(4-aminopiperidin- 1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration. J. Med. Chem. 51, 2147–2157 (2008).
Albert, J. S. et al. An integrated approach to fragment-based lead generation: philosophy, strategy and case studies from AstraZeneca's drug discovery programmes. Curr. Top. Med. Chem. 7, 1600–1629 (2007).
de Graaf, C. et al. Small and colorful stones make beautiful mosaics: fragment-based chemogenomics. Drug Discov. Today 18, 323–330 (2013).
Rasmussen, S. G. et al. Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature 450, 383–387 (2007).
Warne, T. et al. Structure of a β1-adrenergic G-protein-coupled receptor. Nature 454, 486–491 (2008).
Christopher, J. A. et al. Biophysical fragment screening of the β1-adrenergic receptor: identification of high affinity arylpiperazine leads using structure-based drug design. J. Med. Chem. 56, 3446–3455 (2013).
Wolkenberg, S. E. et al. High concentration electrophysiology-based fragment screen: discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors. Bioorg. Med. Chem. Lett. 21, 2646–2649 (2011).
Szollosi, E. et al. Cell-based and virtual fragment screening for adrenergic α2C receptor agonists. Bioorg. Med. Chem. 23, 3991–3999 (2015).
Oltersdorf, T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005).
Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202–208 (2013). This paper discusses the discovery of the second approved FBDD-derived drug.
Petros, A. M. et al. Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein. Bioorg. Med. Chem. Lett. 24, 1484–1488 (2014).
Burke, J. P. et al. Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design. J. Med. Chem. 58, 3794–3805 (2015).
Maurer, T. et al. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc. Nat. Acad. Sci. USA 109, 5299–5304 (2012).
Sun, Q. et al. Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew. Chem. Int. Ed. 51, 6140–6143 (2012).
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).
Winter, J. J. et al. Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation. J. Med. Chem. 58, 2265–2274 (2015).
Patricelli, M. P. et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 6, 316–329 (2016).
Darby, J. F. et al. Discovery of selective small-molecule activators of a bacterial glycoside hydrolase. Angew. Chem. Int. Ed. 53, 13419–13423 (2014). This paper describes the rare discovery of enzyme activators using FBDD.
Jahnke, W. et al. Binding or bending: distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay. J. Am. Chem. Soc. 132, 7043–7048 (2010). This study uses NMR to differentiate allosteric agonists from antagonists.
Davies, T. G., Jhoti, H., Pathuri, P. & Williams, G. in Fragment-based Drug Discovery: Lessons and Outlook. Vol. 67 (eds Erlanson, D. A. & Jahnke, W.) 37–56 (Wiley-VCH, 2016).
Folmer, R. H. Integrating biophysics with HTS-driven drug discovery projects. Drug Discov. Today 21, 491–498 (2016).
Whittaker, M. Picking up the pieces with FBDD or FADD: invest early for future success. Drug Discov. Today 14, 623–624 (2009).
Taylor, S. J. et al. Discovery of potent, selective chymase inhibitors via fragment linking strategies. J. Med. Chem. 56, 4465–4481 (2013).
Palmer, N., Peakman, T. M., Norton, D. & Rees, D. C. Design and synthesis of dihydroisoquinolones for fragment-based drug discovery (FBDD). Org. Biomol. Chem. 14, 1599–1610 (2016).
Murray, J. B., Roughley, S. D., Matassova, N. & Brough, P. A. Off-rate screening (ORS) by surface plasmon resonance. An efficient method to kinetically sample hit to lead chemical space from unpurified reaction products. J. Med. Chem. 57, 2845–2850 (2014).
The Authors thank U. Schopfer and the anonymous reviewers for helpful comments and suggestions on the manuscript.
D.A.E. is a co-founder, employee and shareholder of Carmot Therapeutics, Inc. R.H. is an employee and shareholder of Vernalis (R&D) Ltd. W.J. is an employee and shareholder of Novartis AG. H.J. is an employee of Astex Pharmaceuticals.
The logarithm of partition coefficient between n-octanol and water. cLogP is a measure of lipophilicity.
A chemical structure motif or primary substructure that is common to a group of compounds.
- Michael acceptors
An activated carbon–carbon double bond that is susceptible to nucleophilic attack.
- Surface plasmon resonance
(SPR). An assay that detects binding between a surface- immobilized molecule (such as a protein) and a molecule in solution (such as a fragment).
- Ligand-observed NMR
Detection of ligand binding by nuclear magnetic resonance (NMR) spectroscopy using methods such as saturation transfer difference (STD) NMR (to measure transfer of magnetization between protein and ligand), T1ρ relaxation (to exploit faster relaxation of bound ligands), waterLOGSY (to detect binding by transfer of magnetization between ligand and bound water) or 19F T2 (to detect faster relaxation of fluorinated bound ligands).
A nuclear magnetic resonance (NMR)-based method to detect false positives, such as pan-assay interference compounds (PAINS).
- Pan-assay interference compounds
(PAINS). Compounds containing substructures that give rise to apparent but artefactual activity in assays. The specific mechanisms vary and are not always known, but include forming covalent adducts with the protein or producing hydrogen peroxide.
- Thermal shift assays
(TSAs). Assays, such as differential scanning fluorimetry, that measure the denaturation (or melting) temperature of a protein, which is often increased in the presence of a binding partner.
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Erlanson, D., Fesik, S., Hubbard, R. et al. Twenty years on: the impact of fragments on drug discovery. Nat Rev Drug Discov 15, 605–619 (2016). https://doi.org/10.1038/nrd.2016.109
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