and range of applicability. J Biomol NMR 21
(4):349–359
27. Hajduk PJ, Meadows RP, Fesik SW (1997)
Discovering high-affinity ligands for proteins.
Science 278(5337):497–499
28. Becker W, Bhattiprolu KC, Gubens€ ak N, Zangger K (2018) Investigating protein-ligand
interactions by solution nuclear magnetic resonance spectroscopy. Chemphyschem 19
(8):895–906. https://doi.org/10.1002/cphc.
201701253
29. Meyer B, Peters T (2003) NMR spectroscopy
techniques for screening and identifying ligand
binding to protein receptors. Angew Chem Int
Ed
42(8):864–890.
https://doi.org/10.
1002/anie.200390233
30. Dalvit C, Fasolini M, Flocco M, Knapp S,
Pevarello P, Veronesi M (2002) NMR-based
screening with competition waterÀligand
observed via gradient spectroscopy experiments: detection of high-affinity ligands. J
Med Chem 45(12):2610–2614. https://doi.
org/10.1021/jm011122k
31. Jordan JB, Whittington DA, Bartberger MD,
Sickmier EA, Chen K, Cheng Y, Judd T (2016)
Fragment-linking approach using (19)F NMR
spectroscopy to obtain highly potent and selective inhibitors of β-secretase. J Med Chem 59
(8):3732–3749. https://doi.org/10.1021/
acs.jmedchem.5b01917
32. Arntson KE, Pomerantz WCK (2016) Proteinobserved fluorine NMR: a bioorthogonal
approach for small molecule discovery. J Med
Chem 59(11):5158–5171. https://doi.org/
10.1021/acs.jmedchem.5b01447
33. Renaud J-P, Chung C-w, Danielson UH,
Egner U, Hennig M, Hubbard RE, Nar H
(2016) Biophysics in drug discovery: impact,
challenges and opportunities. Nat Rev Drug
Discov 15:679. https://doi.org/10.1038/
nrd.2016.123
34. Baurin N, Aboul-Ela F, Barril X, Davis B,
Drysdale M, Dymock B, Finch H,
Fromont C, Richardson C, Simmonite H,
Hubbard RE (2004) Design and characterization of libraries of molecular fragments for use
in NMR screening against protein targets. J
Chem Inf Comput Sci 44(6):2157–2166.
https://doi.org/10.1021/ci049806z
35. Chen IJ, Hubbard RE (2009) Lessons for fragment library design: analysis of output from
multiple screening campaigns. J Comput
Aided Mol Des 23(8):603–620. https://doi.
org/10.1007/s10822-009-9280-5
36. Ray PC, Kiczun M, Huggett M, Lim A, Prati F,
Gilbert IH, Wyatt PG (2017) Fragment library
design, synthesis and expansion: nurturing a
synthesis and training platform. Drug Discov
Today 22(1):43–56. https://doi.org/10.
1016/j.drudis.2016.10.005
37. Baell JB, Holloway GA (2010) New substructure filters for removal of pan assay interference
compounds (PAINS) from screening libraries
and for their exclusion in bioassays. J Med
Chem 53(7):2719–2740. https://doi.org/10.
1021/jm901137j
38. Erlanson DA (2018) Poll results: library vendors.
http://practicalfragments.blogspot.
com/2018/12/poll-results-library-vendors.
html
39. Stott K, Stonehouse J, Keeler J, Hwang T-L,
Shaka AJ (1995) Excitation sculpting in highresolution nuclear magnetic resonance spectroscopy: application to selective NOE experiments. J Am Chem Soc 117(14):4199–4200.
https://doi.org/10.1021/ja00119a048
40. Henzel WJ, Watanabe C, Stults JT (2003) Protein identification: the origins of peptide mass
fingerprinting. J Am Soc Mass Spectrom 14
(9):931–942.
https://doi.org/10.1016/
S1044-0305(03)00214-9
41. El-Aneed A, Cohen A, Banoub J (2009) Mass
spectrometry, review of the basics: electrospray,
MALDI, and commonly used mass analyzers.
Appl Spectrosc Rev 44(3):210–230. https://
doi.org/10.1080/05704920902717872
42. Davis BJ, Giannetti AM (2016) The synthesis
of biophysical methods in support of robust
fragment-based Lead discovery. In: Fragmentbased drug discovery lessons and outlook.
Wiley-VCH Verlag GmbH & Co. KGaA,
Weinheim, pp 119–138. https://doi.org/10.
1002/9783527683604.ch06
43. Erlanson DA, Davis BJ, Jahnke W (2018)
Fragment-based drug discovery: advancing
fragments in the absence of crystal structures.
Cell Chem Biol 26:9–15. https://doi.org/10.
1016/j.chembiol.2018.10.001
44. Brough PA, Barril X, Borgognoni J, Chene P,
Davies NG, Davis B, Drysdale MJ, Dymock B,
Eccles SA, Garcia-Echeverria C, Fromont C,
Hayes A, Hubbard RE, Jordan AM, Jensen
MR, Massey A, Merrett A, Padfield A,
Parsons R, Radimerski T, Raynaud FI,
Robertson A, Roughley SD, Schoepfer J,
Simmonite H, Sharp SY, Surgenor A,
Valenti M, Walls S, Webb P, Wood M,
Workman P, Wright L (2009) Combining hit
identification strategies: fragment-based and in
silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the
Hsp90 molecular chaperone. J Med Chem 52
(15):4794–4809. https://doi.org/10.1021/
jm900357y
270
Ben J. Davis
(4):349–359
27. Hajduk PJ, Meadows RP, Fesik SW (1997)
Discovering high-affinity ligands for proteins.
Science 278(5337):497–499
28. Becker W, Bhattiprolu KC, Gubens€ ak N, Zangger K (2018) Investigating protein-ligand
interactions by solution nuclear magnetic resonance spectroscopy. Chemphyschem 19
(8):895–906. https://doi.org/10.1002/cphc.
201701253
29. Meyer B, Peters T (2003) NMR spectroscopy
techniques for screening and identifying ligand
binding to protein receptors. Angew Chem Int
Ed
42(8):864–890.
https://doi.org/10.
1002/anie.200390233
30. Dalvit C, Fasolini M, Flocco M, Knapp S,
Pevarello P, Veronesi M (2002) NMR-based
screening with competition waterÀligand
observed via gradient spectroscopy experiments: detection of high-affinity ligands. J
Med Chem 45(12):2610–2614. https://doi.
org/10.1021/jm011122k
31. Jordan JB, Whittington DA, Bartberger MD,
Sickmier EA, Chen K, Cheng Y, Judd T (2016)
Fragment-linking approach using (19)F NMR
spectroscopy to obtain highly potent and selective inhibitors of β-secretase. J Med Chem 59
(8):3732–3749. https://doi.org/10.1021/
acs.jmedchem.5b01917
32. Arntson KE, Pomerantz WCK (2016) Proteinobserved fluorine NMR: a bioorthogonal
approach for small molecule discovery. J Med
Chem 59(11):5158–5171. https://doi.org/
10.1021/acs.jmedchem.5b01447
33. Renaud J-P, Chung C-w, Danielson UH,
Egner U, Hennig M, Hubbard RE, Nar H
(2016) Biophysics in drug discovery: impact,
challenges and opportunities. Nat Rev Drug
Discov 15:679. https://doi.org/10.1038/
nrd.2016.123
34. Baurin N, Aboul-Ela F, Barril X, Davis B,
Drysdale M, Dymock B, Finch H,
Fromont C, Richardson C, Simmonite H,
Hubbard RE (2004) Design and characterization of libraries of molecular fragments for use
in NMR screening against protein targets. J
Chem Inf Comput Sci 44(6):2157–2166.
https://doi.org/10.1021/ci049806z
35. Chen IJ, Hubbard RE (2009) Lessons for fragment library design: analysis of output from
multiple screening campaigns. J Comput
Aided Mol Des 23(8):603–620. https://doi.
org/10.1007/s10822-009-9280-5
36. Ray PC, Kiczun M, Huggett M, Lim A, Prati F,
Gilbert IH, Wyatt PG (2017) Fragment library
design, synthesis and expansion: nurturing a
synthesis and training platform. Drug Discov
Today 22(1):43–56. https://doi.org/10.
1016/j.drudis.2016.10.005
37. Baell JB, Holloway GA (2010) New substructure filters for removal of pan assay interference
compounds (PAINS) from screening libraries
and for their exclusion in bioassays. J Med
Chem 53(7):2719–2740. https://doi.org/10.
1021/jm901137j
38. Erlanson DA (2018) Poll results: library vendors.
http://practicalfragments.blogspot.
com/2018/12/poll-results-library-vendors.
html
39. Stott K, Stonehouse J, Keeler J, Hwang T-L,
Shaka AJ (1995) Excitation sculpting in highresolution nuclear magnetic resonance spectroscopy: application to selective NOE experiments. J Am Chem Soc 117(14):4199–4200.
https://doi.org/10.1021/ja00119a048
40. Henzel WJ, Watanabe C, Stults JT (2003) Protein identification: the origins of peptide mass
fingerprinting. J Am Soc Mass Spectrom 14
(9):931–942.
https://doi.org/10.1016/
S1044-0305(03)00214-9
41. El-Aneed A, Cohen A, Banoub J (2009) Mass
spectrometry, review of the basics: electrospray,
MALDI, and commonly used mass analyzers.
Appl Spectrosc Rev 44(3):210–230. https://
doi.org/10.1080/05704920902717872
42. Davis BJ, Giannetti AM (2016) The synthesis
of biophysical methods in support of robust
fragment-based Lead discovery. In: Fragmentbased drug discovery lessons and outlook.
Wiley-VCH Verlag GmbH & Co. KGaA,
Weinheim, pp 119–138. https://doi.org/10.
1002/9783527683604.ch06
43. Erlanson DA, Davis BJ, Jahnke W (2018)
Fragment-based drug discovery: advancing
fragments in the absence of crystal structures.
Cell Chem Biol 26:9–15. https://doi.org/10.
1016/j.chembiol.2018.10.001
44. Brough PA, Barril X, Borgognoni J, Chene P,
Davies NG, Davis B, Drysdale MJ, Dymock B,
Eccles SA, Garcia-Echeverria C, Fromont C,
Hayes A, Hubbard RE, Jordan AM, Jensen
MR, Massey A, Merrett A, Padfield A,
Parsons R, Radimerski T, Raynaud FI,
Robertson A, Roughley SD, Schoepfer J,
Simmonite H, Sharp SY, Surgenor A,
Valenti M, Walls S, Webb P, Wood M,
Workman P, Wright L (2009) Combining hit
identification strategies: fragment-based and in
silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the
Hsp90 molecular chaperone. J Med Chem 52
(15):4794–4809. https://doi.org/10.1021/
jm900357y
270
Ben J. Davis