Article | Published:

Natural-product-derived fragments for fragment-based ligand discovery

Nature Chemistry volume 5, pages 2128 (2013) | Download Citation

Abstract

Fragment-based ligand and drug discovery predominantly employs sp2-rich compounds covering well-explored regions of chemical space. Despite the ease with which such fragments can be coupled, this focus on flat compounds is widely cited as contributing to the attrition rate of the drug discovery process. In contrast, biologically validated natural products are rich in stereogenic centres and populate areas of chemical space not occupied by average synthetic molecules. Here, we have analysed more than 180,000 natural product structures to arrive at 2,000 clusters of natural-product-derived fragments with high structural diversity, which resemble natural scaffolds and are rich in sp3-configured centres. The structures of the cluster centres differ from previously explored fragment libraries, but for nearly half of the clusters representative members are commercially available. We validate their usefulness for the discovery of novel ligand and inhibitor types by means of protein X-ray crystallography and the identification of novel stabilizers of inactive conformations of p38α MAP kinase and of inhibitors of several phosphatases.

  • Compound C14H10N2O

    3-Phenylquinazolin-4(3H)-one

  • Compound C15H12O5

    5,7-Dihydroxy-2-(4-hydroxyphenyl)chroman-4-one

  • Compound C12H15NO

    Phenyl(piperidin-1-yl)methanone

  • Compound C13H11NO2

    Benzyl nicotinate

  • Compound C12H10N2O

    N-Phenylnicotinamide

  • Compound C13H12O2

    (3-Phenoxyphenyl)methanol

  • Compound C14H14O2

    (3-(Benzyloxy)phenyl)methanol

  • Compound C12H22N2

    3-Methyldecahydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocine

  • Compound C15H26N2

    (7R,14R)-Tetradecahydro-7,14-methanodipyrido[1,2-a:1',2'-e][1,5]diazocine

  • Compound C18H17ClN2O2

    (1R,5S)-3-(4-Chlorobenzoyl)-3,4,5,6-tetrahydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-8(2H)-one

  • Compound C19H17F3N2O2

    (1R,5S)-3-(4-(Trifluoromethyl)benzoyl)-3,4,5,6-tetrahydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-8(2H)-one

  • Compound C18H18ClN3O2

    (1R,5S)-9-Amino-3-(4-chlorobenzoyl)-3,4,5,6-tetrahydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-8(2H)-one

  • Compound C11H12N2

    2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole

  • Compound C8H16N2

    3-Methyl-3,7-diazabicyclo[3.3.1]nonane

  • Compound C7H8O3

    3-Methoxybenzene-1,2-diol

  • Compound C8H12O4

    5-Hydroxy-5-(1-hydroxybutyl)furan-2(5H)-one

  • Compound C9H8O5

    3-Formyl-2,4-dihydroxy-6-methylbenzoic acid

  • Compound C8H9NO2

    5-Acetyl-1-methylpyridin-2(1H)-one

  • Compound C8H13NO4

    tert-Butyl (2-oxooxetan-3-yl)carbamate

  • Compound C10H12O

    4,4a,5,6-Tetrahydronaphthalen-2(3H)-one

  • Compound C10H14O

    7-Methyl-2,3,7,7a-tetrahydro-1H-inden-5(6H)-one

  • Compound C8H9NO2

    Mandelamide

  • Compound C9H9NO2

    2,5-Dimethoxybenzonitrile

  • Compound C13H12N2O

    2-Amino-N-phenylbenzamide

  • Compound C10H13NO4

    3,4,5-Trimethoxybenzamide

  • Compound C9H12O6

    6-Hydroxy-2,2-dimethyltetrahydrofuro[2',3':4,5]furo[2,3-d][1,3]dioxol-5(3aH)-one

  • Compound C10H9NO2

    Methyl 1H-indole-5-carboxylate

  • Compound C8H9NO2

    Benzyl carbamate

  • Compound C9H16O

    7,7-Dimethylbicyclo[2.2.1]heptan-2-ol

  • Compound C8H10N2O

    1-Benzylurea

  • Compound C10H8N2O

    (1H-Imidazol-1-yl)(phenyl)methanone

  • Compound C12H11NO2

    1,1'-(1H-Indole-1,3-diyl)diethanone

  • Compound C9H9NO2

    3,4-Dimethoxybenzonitrile

  • Compound C8H8N2O2

    Isophthalamide

  • Compound C7H7NO3

    3,5-Dihydroxybenzamide

  • Compound C12H9N5O

    N-(7H-Purin-6-yl)benzamide

  • Compound C10H8O2

    Naphthalene-1,5-diol

  • Compound C8H11NO3

    (5-Hydroxy-6-methylpyridine-3,4-diyl)dimethanol

  • Compound C8H10O3

    2,6-Dimethoxyphenol

  • Compound C10H16O

    1,3,3-Trimethylbicyclo[2.2.1]heptan-2-one

  • Compound C10H10O5

    Dimethyl 5-hydroxyisophthalate

  • Compound C8H8O4

    Methyl 2,4-dihydroxybenzoate

  • Compound C10H12O2

    4-Methylbenzyl acetate

  • Compound C8H8O4

    1-(2,3,4-Trihydroxyphenyl)ethanone

  • Compound C8H9NO3

    Methyl 4-amino-3-hydroxybenzoate

  • Compound C10H20O2

    4-(2-Hydroxypropan-2-yl)-1-methylcyclohexanol

  • Compound C7H7BrO

    4-Bromo-3-methylphenol

  • Compound C9H10O3

    Methyl 2-(4-hydroxyphenyl)acetate

  • Compound C10H8O4

    6,7-Dihydroxy-4-methyl-2H-chromen-2-one

  • Compound C8H8O3

    Methyl 3-hydroxybenzoate

  • Compound C10H16O

    2-Methyl-5-(prop-1-en-2-yl)cyclohex-2-enol

  • Compound C8H7ClO3

    Methyl 3-chloro-4-hydroxybenzoate

  • Compound C9H12O4

    4-(Hydroxymethyl)-2,6-dimethoxyphenol

  • Compound C14H14O2S

    (Sulfonylbis(methylene))dibenzene

  • Compound C6H5BrO2

    2-Bromobenzene-1,4-diol

  • Compound C14H18O6

    6-Methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-7,8-diol

  • Compound C10H18OS

    2-(2-Mercaptopropan-2-yl)-5-methylcyclohexanone

  • Compound C9H10O3

    1-(2,4-Dihydroxy-3-methylphenyl)ethanone

  • Compound C14H15O3P

    Dibenzyl phosphonate

  • Compound C8H6BrN

    5-Bromo-1H-indole

  • Compound C12H12O6

    Benzene-1,2,4-triyl triacetate

  • Compound C9H9BrO3

    Methyl 3-bromo-4-methoxybenzoate

  • Compound C8H6Br2O3

    Methyl 3,5-dibromo-2-hydroxybenzoate

  • Compound C10H12O3

    1-(4-Hydroxy-3-methoxyphenyl)propan-2-one

  • Compound C10H8N2

    2,2'-Bipyridine

  • Compound C15H12O3

    1-(2-Hydroxyphenyl)-3-phenylpropane-1,3-dione

  • Compound C8H11NO2

    2,5-Dimethoxyaniline

  • Compound C8H11NO2

    2,4-Dimethoxyaniline

  • Compound C10H12O3

    4-Methoxybenzyl acetate

  • Compound C9H12O2

    1-(2-Methoxyphenyl)ethanol

  • Compound C10H10O3

    Methyl 4-acetylbenzoate

  • Compound C9H10O3

    1-(2-Hydroxy-4-methoxyphenyl)ethanone

  • Compound C11H12O2

    4-Vinylbenzyl acetate

  • Compound C7H4BrNO

    3-Bromo-4-hydroxybenzonitrile

  • Compound C10H12O3

    2-((4-Methoxyphenoxy)methyl)oxirane

  • Compound C9H9NO4

    2-((4-Nitrophenoxy)methyl)oxirane

  • Compound C10H14O5

    2-Methyl-3,4-dihydro-2H-pyran-3,4-diyl diacetate

  • Compound C7H5NOS

    Benzo[d]thiazol-2-ol

  • Compound C16H16N2O2

    N,N'-(Ethane-1,2-diyl)dibenzamide

  • Compound C10H18O

    5-Methyl-2-(prop-1-en-2-yl)cyclohexanol

  • Compound C10H18O

    2-(4-Methylcyclohex-3-en-1-yl)propan-2-ol

  • Compound C8H10O3

    1-(Furan-2-yl)ethyl acetate

  • Compound C18H28O6

    6'-(1,4-Dioxaspiro[4.5]decan-2-yl)tetrahydrospiro[cyclohexane-1,2'-furo[3,4-d][1,3]dioxol]-4'-ol

  • Compound C5H4N2O4

    2,6-Dihydroxypyrimidine-4-carboxylic acid

  • Compound C10H11NO2

    4-Methyl-5-phenyloxazolidin-2-one

  • Compound C9H9NO2

    3,4-Dihydroisoquinoline-6,7-diol

  • Compound C8H8O3

    Benzo[d][1,3]dioxol-5-ylmethanol

  • Compound C9H16O2

    1,7-Dioxaspiro[5.5]undecane

  • Compound C14H8O4

    1,4-Dihydroxyanthracene-9,10-dione

  • Compound C6H4N4O2

    Pteridine-2,4(1H,3H)-dione

  • Compound C10H12O3

    Methyl 2-(3-methoxyphenyl)acetate

  • Compound C8H6Cl2O2

    1-(3,5-Dichloro-2-hydroxyphenyl)ethanone

  • Compound C10H11NO6

    Methyl 4,5-dimethoxy-2-nitrobenzoate

  • Compound C12H10O2

    1-(2-Hydroxynaphthalen-1-yl)ethanone

  • Compound C10H9BrO4

    2-Bromo-1,4-phenylene diacetate

  • Compound C8H7NOS

    3-Methylbenzo[d]thiazol-2(3H)-one

  • Compound C12H12N2O

    1-Methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-7-ol

  • Compound C6H7N3O2

    N-(2-Oxo-1,2-dihydropyrimidin-4-yl)acetamide

  • Compound C8H6O3

    3-Hydroxyisobenzofuran-1(3H)-one

  • Compound C10H9NO2

    Methyl 1H-indole-3-carboxylate

  • Compound C12H22O

    (1S,2S,4R)-1,3,3,7,7-Pentamethylbicyclo[2.2.1]heptan-2-ol

  • Compound C8H15NO

    8-Methyl-8-azabicyclo[3.2.1]octan-3-ol

  • Compound C10H18O2

    1,7,7-Trimethylbicyclo[2.2.1]heptane-2,3-diol

  • Compound C8H12O5

    6-(Hydroxymethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one

  • Compound C8H11ClO4

    6-(Chloromethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one

  • Compound C10H18O6

    1-(2,6-Dimethyltetrahydro-[1,3]dioxino[5,4-d][1,3]dioxin-4-yl)ethane-1,2-diol

  • Compound C6H11NO2

    Piperidine-2-carboxylic acid

  • Compound C11H19NO4

    1-(tert-Butoxycarbonyl)piperidine-2-carboxylic acid

  • Compound C4H6O4

    3,4-Dihydroxydihydrofuran-2(3H)-one

  • Compound C6H10N2O2

    3,6-Dimethylpiperazine-2,5-dione

  • Compound C4H6N2O2

    Piperazine-2,5-dione

  • Compound C7H12N2O2

    3-Isopropylpiperazine-2,5-dione

  • Compound C10H21N

    N,N-Diethylcyclohexanamine

  • Compound C13H11N3O4

    1,3-Dioxo-2-phenyl-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-5-carboxylic acid

  • Compound C13H13N3O4

    1,3-Dioxo-2-phenylhexahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-5-carboxylic acid

  • Compound C12H15N3O3

    2-(Phenylcarbamoyl)hexahydropyridazine-3-carboxylic acid

  • Compound C10H19N

    N,N-Diethylcyclohex-2-enamine

  • Compound C8H10O6

    2-Oxotetrahydrofuran-3,4-diyl diacetate

  • Compound C3H4N2O2

    Imidazolidine-2,4-dione

  • Compound C5H6N2O3

    1-Acetylimidazolidine-2,4-dione

  • Compound C5H7NO3

    5-Oxopyrrolidine-2-carboxylic acid

  • Compound C7H13NO2

    2-Aminocyclohexanecarboxylic acid

  • Compound C10H13NO

    6-Methoxy-1,2,3,4-tetrahydroquinoline

  • Compound C5H10O2

    (Tetrahydrofuran-2-yl)methanol

  • Compound C13H24O3

    2-Isopropyl-5-methylcyclohexyl 2-hydroxypropanoate

  • Compound C10H16O4

    Dimethyl cyclohexane-1,4-dicarboxylate

  • Compound C8H14O5

    Methyl 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate

  • Compound C12H22N2O4

    tert-Butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate

  • Compound C9H16N2O2

    Piperazin-1-yl(tetrahydrofuran-2-yl)methanone

  • Compound C13H22O

    2,6,10,10-Tetramethyl-1-oxaspiro[4.5]dec-6-ene

  • Compound C5H11NO

    (Tetrahydrofuran-2-yl)methanamine

  • Compound C10H16

    4,7,7-Trimethylbicyclo[4.1.0]hept-2-ene

  • Compound C10H19NO

    (5-Ethylquinuclidin-2-yl)methanol

  • Compound C7H14O4

    (2,2-Dimethyl-1,3-dioxolane-4,5-diyl)dimethanol

  • Compound C8H17NO2

    3-(Piperidin-1-yl)propane-1,2-diol

  • Compound C15H26O

    1,1,4,7-Tetramethyldecahydro-1H-cyclopropa[e]azulen-4-ol

  • Compound C6H11F3N2O2S

    1,1,1-Trifluoro-N-(pyrrolidin-2-ylmethyl)methanesulfonamide

  • Compound C10H18O

    1,3,3-Trimethyl-2-oxabicyclo[2.2.2]octane

  • Compound C10H18O

    (E)-5-(But-2-en-2-yl)-2,2-dimethyltetrahydrofuran

  • Compound C13H25NO3

    tert-Butyl (1-cyclohexyl-2-hydroxyethyl)carbamate

  • Compound C10H18O2

    2-(5-Methyl-5-vinyltetrahydrofuran-2-yl)propan-2-ol

  • Compound C6H12O

    2,5-Dimethyltetrahydrofuran

  • Compound C10H16O

    1-Methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptane

  • Compound C7H12O4

    2,2,5-Trimethyl-1,3-dioxolane-4-carboxylic acid

  • Compound C10H18O

    5-Isopropyl-2-methylbicyclo[3.1.0]hexan-2-ol

  • Compound C9H15NO4

    1-(tert-Butoxycarbonyl)azetidine-2-carboxylic acid

  • Compound C9H16O4

    Ethyl 2-(2,4-dimethyl-1,3-dioxolan-2-yl)acetate

  • Compound C9H18N2

    1-(Pyrrolidin-2-ylmethyl)pyrrolidine

  • Compound C10H22N2

    4-(2-Aminopropan-2-yl)-1-methylcyclohexanamine

  • Compound C10H18O

    1,7,7-Trimethylbicyclo[2.2.1]heptan-2-ol

  • Compound C14H8O4

    1,4-Dihydroxyanthracene-9,10-dione

  • Compound C15H12O3

    1,8-Dihydroxy-3-methylanthracen-9(10H)-one

  • Compound C13H11NO3

    8-Methoxy-9-methylfuro[2,3-b]quinolin-4(9H)-one

  • Compound C11H10O2

    (2E,4E)-5-Phenylpenta-2,4-dienoic acid

  • Compound C8H8O3

    2-Hydroxy-6-methylbenzoic acid

  • Compound C14H12O3

    (E)-5-(4-Hydroxystyryl)benzene-1,3-diol

  • Compound C13H12O3

    1-(6-Hydroxy-2-(prop-1-en-2-yl)benzofuran-5-yl)ethanone

  • Compound C14H10O3

    2-Methoxy-9H-xanthen-9-one

  • Compound C14H12O4

    (2,3-Dihydroxy-4-methoxyphenyl)(phenyl)methanone

  • Compound C12H14N2O2

    3-(1H-Indol-3-yl)-2-(methylamino)propanoic acid

  • Compound C11H11NO2

    5-Benzyl-4-hydroxy-1H-pyrrol-2(5H)-one

  • Compound C6H7NO3

    (E)-3-(1-Hydroxyethylidene)pyrrolidine-2,4-dione

  • Compound C17H15NO2

    3-(3-Phenyl-1H-indol-2-yl)propanoic acid

  • Compound C14H18N2O

    7-Methoxy-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

  • Compound C20H18N2O6

    3,3'-((9,10-Dioxo-9,10-dihydroanthracene-1,4-diyl)bis(azanediyl))dipropanoic acid

  • Compound C11H8O6

    2,3,5,8-Tetrahydroxy-6-methylnaphthalene-1,4-dione

  • Compound C10H6O3

    2-Hydroxynaphthalene-1,4-dione

  • Compound C10H6O3

    5-Hydroxynaphthalene-1,4-dione

  • Compound C19H23F3N4O3

    (E)-2-(4-Nitrophenyl)-4-((octylimino)methyl)-5-(trifluoromethyl)-1H-pyrazol-3(2H)-one

  • Compound C21H32N4O3

    1-(3-(3,3-Dimethylbutanoyl)-8-oxo-2,3,4,5,6,8-hexahydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-9-yl)-3-isopropylurea

  • Compound C24H26O6

    1,3,6-Trihydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one

  • Compound C20H23NO4

    1,2,10-Trimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-ol

  • Compound C19H21NO3

    6-Propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2,10,11-triol

  • Compound C19H19NO2

    6-Allyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol

  • Compound C17H17NO2

    6-Methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol

  • Compound C13H12INO2

    3-(1-(4-Iodophenyl)-1H-pyrrol-2-yl)propanoic acid

  • Compound C14H15NO2

    3-(1-Benzyl-1H-pyrrol-2-yl)propanoic acid

  • Compound C22H34O4

    8-Acetoxy-4,9,11b-trimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylic acid

  • Compound C7H7F3N2S

    N-Allyl-4-(trifluoromethyl)thiazol-2-amine

  • Compound C12H16O2

    8,8a-Dimethyl-3,4,8,8a-tetrahydronaphthalene-1,6(2H,7H)-dione

  • Compound C12H16O2

    3,5-Dimethyl-3,4,8,8a-tetrahydronaphthalene-1,6(2H,7H)-dione

  • Compound C20H31NO5S

    (2Z,6Z)-10-(6-Hydroxy-4-methyl-6-(2-oxothiazolidin-4-yl)tetrahydro-2H-pyran-2-yl)-8-methyldeca-2,6-dienoic acid

  • Compound C14H10ClNO4

    3-(4-Chlorobenzamido)-2-hydroxybenzoic acid

  • Compound C8H9N5O2

    1,3,6-Trimethylpyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione

  • Compound C17H18O3

    2,3,5-Trimethyl-6-propyl-7H-furo[3,2-g]chromen-7-one

  • Compound C12H20O4

    5-Hydroxy-4-(1-hydroxyoctyl)furan-2(5H)-one

  • Compound C8H14O4

    1-(2,5-Dimethoxy-2,5-dihydrofuran-2-yl)ethanol

  • Compound C10H18O4

    1-(2,5-Dimethoxy-2,5-dimethyl-2,5-dihydrofuran-3-yl)ethanol

  • Compound C12H20O4

    5-Hydroxy-5-(1-hydroxyoctyl)furan-2(5H)-one

  • Compound C22H40O4

    5-Hydroxy-5-(1-hydroxyoctadecyl)furan-2(5H)-one

  • Compound C16H28O4

    5-Hydroxy-5-(1-hydroxydodecyl)furan-2(5H)-one

  • Compound C15H26O4

    5-Hydroxy-5-(6-hydroxyundecan-6-yl)furan-2(5H)-one

  • Compound C13H23NO5

    N-((2,5-Dimethoxy-2,5-dihydrofuran-2-yl)methyl)-6-hydroxyhexanamide

  • Compound C11H13N3O3

    (1R,5S)-9-Nitro-3,4,5,6-tetrahydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-8(2H)-one

  • Compound C18H16ClN3O4

    (1R,5S)-3-(4-Chlorobenzoyl)-9-nitro-3,4,5,6-tetrahydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-8(2H)-one

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & The rise of fragment-based drug discovery. Nature Chem. 1, 187–192 (2009).

  2. 2.

    & How well can fragments explore accessed chemical space? A case study from heat shock protein 90. J. Med. Chem. 54, 3989–4005 (2011).

  3. 3.

    & From fragment to clinical candidate—a historical perspective. Drug Discov. Today 14, 668–675 (2009).

  4. 4.

    & Deconstructing fragment-based inhibitor discovery. Nature Chem. Biol. 2, 720–723 (2006).

  5. 5.

    , & Informatics and modeling challenges in fragment-based drug discovery. Curr. Opin. Drug Discov. Dev. 10, 289–297 (2007).

  6. 6.

    & Drugs in other drugs: a new look at drugs as fragments. Drug Discov. Today 12, 71–79 (2007).

  7. 7.

    et al. Molecular shape and medicinal chemistry: a perspective. J. Med. Chem. 53, 3862–3886 (2010).

  8. 8.

    , , & The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types. Drug Discov. Today 16, 164–171 (2011).

  9. 9.

    , & Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

  10. 10.

    et al. Route to three-dimensional fragments using diversity-oriented synthesis. Proc. Natl Acad. Sci. USA 108, 6799–6804 (2011).

  11. 11.

    & Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75, 311–335 (2012).

  12. 12.

    , , , & Cheminformatic analysis of natural products and their chemical space. Chimia Int. J. Chem. 61, 355–360 (2007).

  13. 13.

    , & Scaffold diversity of natural products: inspiration for combinatorial library design. Nat. Prod. Rep. 25, 892–904 (2008).

  14. 14.

    , , & A ‘Rule of Three’ for fragment-based lead discovery? Drug Discov. Today 8, 876–877 (2003).

  15. 15.

    et al. A small nonrule of 3 compatible fragment library provides high hit rate of endothiapepsin crystal structures with various fragment chemotypes. J. Med. Chem. 54, 7784–7796 (2011).

  16. 16.

    , , & Biology-oriented synthesis. Angew. Chem. Int. Ed. 50, 10800–10826 (2011).

  17. 17.

    & Bioactivity-guided navigation of chemical space. Acc. Chem. Res. 43, 1103–1114 (2010).

  18. 18.

    & Synthesis of natural product inspired compound collections. Angew. Chem. Int. Ed. 48, 3224–3242 (2009).

  19. 19.

    et al. The scaffold tree; visualization of the scaffold universe by hierarchical scaffold classification. J. Chem. Inf. Model. 47, 47–58 (2007).

  20. 20.

    et al. Charting biologically relevant chemical space: a structural classification of natural products (SCONP). Proc. Natl Acad. Sci. USA 102, 17272–17277 (2005).

  21. 21.

    Dictionary of Natural Products Version 18.2, 2009 (Chapman & Hall/CRC Press, 2009).

  22. 22.

    & The properties of known drugs. 1. Molecular frameworks. J. Med. Chem. 39, 2887–2893 (1996).

  23. 23.

    , , , & ZINC: a free tool to discover chemistry for biology. J. Chem. Inf. Model. 52, 1757–1768 (2012).

  24. 24.

    Unsupervised data base clustering based on daylight's fingerprint and Tanimoto similarity: a fast and automated way to cluster small and large data sets. J. Chem. Inf. Comput. Sci. 39, 747–750 (1999).

  25. 25.

    et al. Identification of novel p38α MAP kinase inhibitors using fragment-based lead generation. J. Med. Chem. 48, 414–426 (2004).

  26. 26.

    et al. A comparative study of fragment screening methods on the p38α kinase: new methods, new insights. J. Comput. Aided Molec. Des. 25, 677–687 (2011).

  27. 27.

    , , , & Biological evaluation and structural determinants of p38α mitogen-activated-protein kinase and c-Jun-N-terminal kinase 3 inhibition by flavonoids. ChemBioChem 11, 2579–2588 (2010).

  28. 28.

    , & Evaluation of (+)-sparteine-like diamines for asymmetric synthesis. J. Org. Chem. 69, 5789–5792 (2004).

  29. 29.

    et al. A new screening assay for allosteric inhibitors of cSrc. Nature Chem. Biol. 5, 394–396 (2009).

  30. 30.

    et al. Proteus in the world of proteins: conformational changes in protein kinases. Arch. Pharm. (Weinheim) 343, 193–206 (2010).

  31. 31.

    et al. Switch control pocket inhibitors of p38–MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region. Bioorg. Med. Chem. Lett. 20, 5793–5798 (2010).

  32. 32.

    et al. Biochemical and biophysical characterization of unique switch pocket inhibitors of p38α. Bioorg. Med. Chem. Lett. 20, 5787–5792 (2010).

  33. 33.

    et al. Structure-based design, synthesis and biological evaluation of N-pyrazole, N′-thiazole urea inhibitors of MAP kinase p38α. Eur. J. Med. Chem. 48, 1–15 (2012).

  34. 34.

    , , & Biology-inspired synthesis of compound libraries. Cell. Mol. Life Sci. 65, 1186–1201 (2008).

  35. 35.

    , , & The therapeutic potential of phosphatase inhibitors. Curr. Opin. Chem. Biol. 13, 272–283 (2009).

  36. 36.

    , & Using small molecules to target protein phosphatases. Bioorg. Med. Chem. 19, 2145–2155 (2011).

  37. 37.

    & Inhibitors of protein tyrosine phosphatases: next-generation drugs? Angew. Chem. Int. Ed. 44, 3814–3839 (2005).

  38. 38.

    et al. Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis. Proc. Natl Acad. Sci. USA 103, 10606–10611 (2006).

  39. 39.

    et al. Bioactivity-guided mapping and navigation of chemical space. Nature Chem. Biol. 5, 585–592 (2009).

  40. 40.

    , , , & Quantifying biogenic bias in screening libraries. Nature Chem. Biol. 5, 479–483 (2009).

  41. 41.

    & The scaffold hopping potential of pharmacophores. Drug Discov. Today: Technologies 7, e263–e269 (2010).

  42. 42.

    & Fragment shuffling: an automated workflow for three-dimensional fragment-based ligand design. J. Chem. Inf. Model. 49, 1211–1222 (2009).

  43. 43.

    , , , & Selectivity of kinase inhibitor fragments. J. Med. Chem. 54, 5131–5143 (2011).

  44. 44.

    , , & Mining for bioactive scaffolds with scaffold networks: improved compound set enrichment from primary screening data. J. Chem. Inf. Model. 51, 1528–1538 (2011).

  45. 45.

    et al. Interactive exploration of chemical space with scaffold hunter. Nature Chem. Biol. 5, 581–583 (2009).

  46. 46.

    et al. Recent developments of the chemistry development kit (CDK)—an open-source Java library for chemo- and bioinformatics. Curr. Pharmaceut. Des. 1217, 2111–2120 (2006).

Download references

Acknowledgements

The research leading to these results was supported by funding from the European Research Council (ERC) under the European Union's Seventh Framework Program (FP7/ 2007-2013) and ERC grant agreement no. 268309, from the German Federal Ministry for Education and Research through the German National Genome Research Network-Plus (NGFN-Plus) (grant no. BMBF 01GS08104 to H.W. and D.R.), as well as from the Fonds der Chemischen Industrie.

Author information

Author notes

    • Yasushi Nakai
    •  & Steffen Renner

    Present address: Novartis Institute of Biomedical Research, Basel, Switzerland (S.R.); Shionogi Pharmaceutical Research Center 3-1-1, Futaba-cho, Toyonaka-shi, Osaka 561-0825, Japan (Y.N.)

Affiliations

  1. Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany

    • Björn Over
    • , Stefan Wetzel
    • , Yasushi Nakai
    • , Steffen Renner
    •  & Herbert Waldmann
  2. Technische Universität Dortmund, Fakultät Chemie, Chemische Biologie, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany

    • Björn Over
    • , Christian Grütter
    • , Daniel Rauh
    •  & Herbert Waldmann
  3. Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany

    • Christian Grütter
    •  & Daniel Rauh

Authors

  1. Search for Björn Over in:

  2. Search for Stefan Wetzel in:

  3. Search for Christian Grütter in:

  4. Search for Yasushi Nakai in:

  5. Search for Steffen Renner in:

  6. Search for Daniel Rauh in:

  7. Search for Herbert Waldmann in:

Contributions

B.O. and Y.N. performed computational experiments and syntheses. S.W. and S.R. performed computational experiments. B.O. performed biochemical experiments. B.O. and C.G. determined crystal structure analyses. B.O., S.W., D.R. and H.W. designed experiments. D.R. and H.W. supervised the research. B.O., S.W., D.R. and H.W. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Herbert Waldmann.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    Supplementary information

  2. 2.

    Supplementary information

    Representative natural product fragment library

  3. 3.

    Supplementary information

    Supplementary Table S1 - Summary of commercially available fragments

Structured data files

  1. 1.

    Supplementary information

    Structure data file for representative natural product fragment library

  2. 2.

    Supplementary information

    Structure data file for Supplementary Table S1

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nchem.1506

Further reading