Abstract

The structure- and chemistry-based hierarchical organization of library scaffolds in tree-like arrangements provides a valid, intuitive means to map and navigate chemical space. We demonstrate that scaffold trees built using bioactivity as the key selection criterion for structural simplification during tree construction allow efficient and intuitive mapping, visualization and navigation of the chemical space defined by a given library, which in turn allows correlation of this chemical space with the investigated bioactivity and further compound design. Brachiation along the branches of such trees from structurally complex to simple scaffolds with retained yet varying bioactivity is feasible at high frequency for the five major pharmaceutically relevant target classes and allows for the identification of new inhibitor types for a given target. We provide proof of principle by identifying new active scaffolds for 5-lipoxygenase and the estrogen receptor ERα.

  • Compound

    Paclitaxel

  • Compound

    (alpha-R,beta-S)-beta-(Benzoylamino)-alpha-hydroxy-benzenepropanoic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-bis(acetyloxy)-12-[2-[(3-furanyl)oxy]benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester

  • Compound

    Docetaxel

  • Compound

    (alpha-R,beta-S)-beta-[[(1,1-Dimethylethoxy)carbonyl]amino]-alpha-hydroxy-(4,4-dimethyl)-pentanoic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester

  • Compound

    (2,4-Dimethyl-azetidin-1-yl)-(7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinolin-9-yl)-methanone

  • Compound

    7-Methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carboxylic acid (1-methyl-pentyl)-amide

  • Compound

    1-(4-Dipropylamino-1,3,4,5-tetrahydro-benzo[cd]indol-6-yl)-ethanone

  • Compound

    Yohimbine

  • Compound

    1,2,3,4,6,7,12,12b-Octahydro-indolo[2,3-a]quinolizine

  • Compound

    8-Bromo-2,3,4,9-tetrahydro-1H-beta-carboline

  • Compound

    3-(2-Amino-ethyl)-1H-indol-5-ol

  • Compound

    2-(2,5-Dimethoxy-4-trifluoromethyl-phenyl)-1-methyl-ethylamine

  • Compound

    (1S,5R,13R,14R,17S)-14-(9-Anthracenylmethyl)hydroxy-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10-triene

  • Compound

    (1S,5R,13R,14R,17S)-14-(1-Naphthylmethyl)hydroxy-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10-triene

  • Compound

    (1S,5R,13R,14R,17S)-14-Benzylhydroxy-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10-triene

  • Compound

    (1S,5R,13R,14R,17S)-14-Bromo-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.01,13.05,17.07,18]octadeca-7(18),8,10-triene

  • Compound

    (-)-17-(Cyclopropylmethyl)morphinan-3-ol

  • Compound

    (-)-17-(2-Propynyl)morphinan-3-ol

  • Compound

    3-Allyl-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ol

  • Compound

    7-Diallylamino-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol

  • Compound

    2-(3,4-Dichloro-phenyl)-N-{1-[(isopropyl-methyl-amino)-methyl]-2-methyl-propyl}-N-methyl-acetamide

  • Compound

    N-((7S,11S)-3-Chloro-9-methyl-6,7,8,9,10,11-hexahydro-7,11-methanocycloocta[b]quinolin-12-yl)-N'-(1,2,3,4-tetrahydro-acridin-9-yl)-heptane-1,7-diamine

  • Compound

    N,N'-Bis-(6-chloro-1,2,3,4-tetrahydro-acridin-9-yl)-heptane-1,7-diamine

  • Compound

    N-Quinolin-4-yl-N'-(1,2,3,4-tetrahydro-acridin-9-yl)-heptane-1,7-diamine

  • Compound

    N-Pyridin-4-yl-N'-(1,2,3,4-tetrahydro-acridin-9-yl)-heptane-1,7-diamine

  • Compound

    1,2,3,4-Tetrahydro-acridin-9-ylamine

  • Compound

    Propionic acid 4-amino-5-fluoro-2-methyl-quinolin-3-yl ester

  • Compound

    Neostigmine

  • Compound

    3-[3-(4-Benzoyl-piperazin-1-yl)-2-(naphthalene-2-sulfonylamino)-3-oxo-propyl]-benzamidine

  • Compound

    3-[3-[4-(Naphthalene-2-carbonyl)-piperazin-1-yl]-2-(naphthalene-2-sulfonylamino)-3-oxo-propyl]-benzamidine

  • Compound

    4-[3-(3-Carbamimidoyl-phenyl)-2-(naphthalene-2-sulfonylamino)-propionyl]-piperazine-1-carboxylic acid methyl ester

  • Compound

    3-(3-Carbamimidoyl-phenyl)-2-(naphthalene-2-sulfonylamino)-propionic acid butyl ester

  • Compound

    3-(3-Carbamimidoyl-phenyl)-N-methyl-2-(2,4,6-triisopropyl-benzenesulfonylamino)-propionamide

  • Compound

    Benzamidine

  • Compound

    Lurtotecan

  • Compound

    (8S)-8-ethyl-2,3-dihydro-8-hydroxy-15-(chloromethyl)-11H-1,4-dioxino(2,3-g)pyrano(3',4':6,7)indolizino(1,2-b)quinoline-9,12(8H,14H)-dione

  • Compound

    Camptothecin

  • Compound

    2-Hydroxy-2-(8-hydroxymethyl-9-oxo-9,11-dihydro-indolizino[1,2-b]quinolin-7-yl)-butyric acid

  • Compound

    4-Furan-3-yl-7-[3-(3-hydroxy-6,8-dioxa-bicyclo[3.2.1]oct-3-yl)-benzyloxy]-3H-naphtho[2,3-c]furan-1-one

  • Compound

    4-Furan-3-yl-7-[3-(3-hydroxy-6,8-dioxa-bicyclo[3.2.1]oct-3-yl)-benzyloxy]-naphthalene-2-carbonitrile

  • Compound

    4-Furan-3-yl-7-[3-(4-hydroxy-tetrahydro-pyran-4-yl)-benzyloxy]-naphthalene-2-carbonitrile

  • Compound

    4-Methoxy-4-[3-(naphthalen-2-yloxymethyl)-phenyl]-tetrahydropyran

  • Compound

    2-Benzyloxynaphthalene

  • Compound

    1-{1-[4-(benzyloxy)phenyl]ethyl}-1-hydroxyurea

  • Compound

    2-(4-Isobutyl-phenyl)-propionic acid

  • Compound

    2-(Naphthalene-2-sulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1,2,3,4-tetrahydro-isoquinolin-6-ol

  • Compound

    2-Benzenesulfonyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1,2,3,4-tetrahydro-isoquinolin-6-ol

  • Compound

    2,2,2-Trifluoro-1-{6-hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethanone

  • Compound

    2,2,2-Trifluoro-1-[6-hydroxy-1-(4-hydroxy-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone

  • Compound

    1,2,3,4-Tetrahydro-isoquinoline

  • Compound

    1-(4-Hydroxy-phenyl)-propan-1-one

  • Compound

    N-(2-Dimethylamino-ethyl)-4-(naphthalen-2-yloxymethyl)-benzamide

  • Compound

    3-(6-Benzyloxy-naphthalen-2-yl)-acrylic acid methyl ester

  • Compound

    4-(6-Bromo-naphthalen-2-yloxymethyl)-phenylamine

  • Compound

    1-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethanone

  • Compound

    1-(3,4-Dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone

  • Compound

    2-Methanesulfonyl-1,2,3,4-tetrahydro-isoquinoline

  • Compound

    1,2,3,4-Tetrahydro-isoquinolin-6-ol

  • Compound

    1-(6-Hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone

  • Compound

    2,2,2-Trifluoro-1-(6-hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone

  • Compound

    2-Methanesulfonyl-1,2,3,4-tetrahydro-isoquinolin-6-ol

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Acknowledgements

This research was supported by the Max-Planck-Gesellschaft and the Fonds der Chemischen Industrie. Part of this work was supported by US National Institutes of Health grants 1R01CA127731 and 1U54MH084690 (to T.I.O.) and by the German Federal Ministry for Education and Research through the German National Genome Research Network-Plus (grant number BMBF 01GS08102, to D.R. and H.W.). W.A.L.v.O. thanks the Alexander von Humboldt Foundation for a Georg Forster Research Fellowship for Experienced Researchers.

Author information

Author notes

    • Steffen Renner

    Present address: Novartis AG, Novartis Institutes for BioMedical Research, Basel, Switzerland.

Affiliations

  1. Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Dortmund, Germany.

    • Steffen Renner
    • , Willem A L van Otterlo
    • , Stefan Wetzel
    •  & Herbert Waldmann
  2. Technische Universität Dortmund, Fakultät Chemie, Dortmund, Germany.

    • Steffen Renner
    • , Stefan Wetzel
    •  & Herbert Waldmann
  3. Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa.

    • Willem A L van Otterlo
  4. Chemical Genomics Centre of the Max-Planck-Society, Dortmund, Germany.

    • Marta Dominguez Seoane
    • , Sabine Möcklinghoff
    • , Luc Brunsveld
    •  & Daniel Rauh
  5. Institute of Pharmaceutical Chemistry, Center for Drug Research, Development and Safety, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.

    • Bettina Hofmann
    •  & Dieter Steinhilber
  6. Novartis Institutes for BioMedical Research, Basel, Switzerland.

    • Ansgar Schuffenhauer
    •  & Peter Ertl
  7. Division of Biocomputing, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.

    • Tudor I Oprea
  8. Technische Universiteit Eindhoven, Department of Biomedical Engineering, Eindhoven, the Netherlands.

    • Luc Brunsveld

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Competing interests

T.I.O. is the owner of Sunset Molecular, the distributor of the WOMBAT database that we used in our studies.

Corresponding author

Correspondence to Herbert Waldmann.

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DOI

https://doi.org/10.1038/nchembio.188

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