Ligand discovery from a dopamine D3 receptor homology model and crystal structure

Journal name:
Nature Chemical Biology
Volume:
7,
Pages:
769–778
Year published:
DOI:
doi:10.1038/nchembio.662
Received
Accepted
Published online

Abstract

G protein–coupled receptors (GPCRs) are intensely studied as drug targets and for their role in signaling. With the determination of the first crystal structures, interest in structure-based ligand discovery increased. Unfortunately, for most GPCRs no experimental structures are available. The determination of the D3 receptor structure and the challenge to the community to predict it enabled a fully prospective comparison of ligand discovery from a modeled structure versus that of the subsequently released crystal structure. Over 3.3 million molecules were docked against a homology model, and 26 of the highest ranking were tested for binding. Six had affinities ranging from 0.2 to 3.1 μM. Subsequently, the crystal structure was released and the docking screen repeated. Of the 25 compounds selected, five had affinities ranging from 0.3 to 3.0 μM. One of the new ligands from the homology model screen was optimized for affinity to 81 nM. The feasibility of docking screens against modeled GPCRs more generally is considered.

At a glance

Figures

  1. Predicted structure of the dopamine D3 receptor binding site.
    Figure 1: Predicted structure of the dopamine D3 receptor binding site.

    (a) Comparison of the homology model of the dopamine D3 receptor in complex with eticlopride (light blue) to the crystal structure (yellow), visualized with PyMOL. The structures have been aligned using 15 binding-site residues. Polar interactions for the crystal structure are shown in black dashed lines. (b) Chemical structure of eticlopride (compound 1).

  2. Predicted binding modes of ligands found from the homology model screen.
    Figure 2: Predicted binding modes of ligands found from the homology model screen.

    (ad) Predicted binding poses for four ligands discovered in the docking screen against the dopamine D3 receptor homology model, visualized with University of California San Francisco (UCSF) Chimera: 3 (a), 4 (b), 6 (c) and 7 (d). (e,f) Predicted binding modes for the two analogs of 3 based on docking to the homology model: 56 (e) and 57 (f). TM, transmembrane helices; EL2, extracellular loop 2.

  3. Dose-response curves of discovered ligands.
    Figure 3: Dose-response curves of discovered ligands.

    (af) Representative radioligand ([3H]N-Methylspiperone) competition binding isotherms for compounds 3 (a), 4 (b), 7 (c), 28 (d), 30 (e) and 31 (f). Data for a reference compound (chlorpromazine, black curve) are shown along with data for the test compound (red curve). Assays are performed using a final radioligand concentration between 0.5 × KD and 1 × KD, where KD equals the radioligand dissociation constant, which is determined for each crude membrane preparation by radioligand saturation binding analysis. Data represent mean values ± s.e.m, performed on triplicate experiments.

  4. Predicted binding modes of ligands found from the crystal structure screen.
    Figure 4: Predicted binding modes of ligands found from the crystal structure screen.

    Predicted binding poses for the ligands discovered in the docking screen against the dopamine D3 receptor crystal structure, visualized with UCSF Chimera: 28 (a), 29 (b), 31 (c) and 32 (d).

Compounds

72 compounds View all compounds
  1. Eticlopride
    Compound 1 Eticlopride
  2. Methyl 3-[[4-(1H-indol-3-yl)piperidin-1-ium-1-yl]methyl]furan-2-carboxylate
    Compound 2 Methyl 3-[[4-(1H-indol-3-yl)piperidin-1-ium-1-yl]methyl]furan-2-carboxylate
  3. [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-(1,3-dihydroxy-2-methylpropan-2-yl)azanium
    Compound 3 [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-(1,3-dihydroxy-2-methylpropan-2-yl)azanium
  4. (1S)-2-[4-(1,2-Benzothiazol-3-yl)piperazin-1-ium-1-yl]-1-thiophen-2-ylethanol
    Compound 4 (1S)-2-[4-(1,2-Benzothiazol-3-yl)piperazin-1-ium-1-yl]-1-thiophen-2-ylethanol
  5. 2-[4-[2-(2-Phenylphenoxy)ethyl]piperazin-4-ium-1-yl]ethanol
    Compound 5 2-[4-[2-(2-Phenylphenoxy)ethyl]piperazin-4-ium-1-yl]ethanol
  6. [5-(4-Fluorophenyl)furan-2-yl]methyl-[(2-pyrazol-1-ylpyridin-3-yl)methyl]azanium
    Compound 6 [5-(4-Fluorophenyl)furan-2-yl]methyl-[(2-pyrazol-1-ylpyridin-3-yl)methyl]azanium
  7. (1S)-1-(2-Fluorophenyl)-2-[4-(3-methylphenyl)piperazin-1-ium-1-yl]ethanol
    Compound 7 (1S)-1-(2-Fluorophenyl)-2-[4-(3-methylphenyl)piperazin-1-ium-1-yl]ethanol
  8. 7-Hydroxy-6-(pyrrolidin-1-ium-1-ylmethyl)-2,3-dihydro-1H-cyclopenta[c]chromen-4-one
    Compound 8 7-Hydroxy-6-(pyrrolidin-1-ium-1-ylmethyl)-2,3-dihydro-1H-cyclopenta[c]chromen-4-one
  9. (1S)-2-[4-(3-Fluorophenoxy)piperidin-1-ium-1-yl]-1-thiophen-2-ylethanol
    Compound 9 (1S)-2-[4-(3-Fluorophenoxy)piperidin-1-ium-1-yl]-1-thiophen-2-ylethanol
  10. (4-Imidazol-1-ylphenyl)methyl-[[2-(1,2,4-triazol-1-ylmethyl)phenyl]methyl]azanium
    Compound 10 (4-Imidazol-1-ylphenyl)methyl-[[2-(1,2,4-triazol-1-ylmethyl)phenyl]methyl]azanium
  11. 1-[(2S)-2-Methyl-2,3-dihydroindol-1-yl]-3-(4-methylpiperidin-1-ium-1-yl)propan-1-one
    Compound 11 1-[(2S)-2-Methyl-2,3-dihydroindol-1-yl]-3-(4-methylpiperidin-1-ium-1-yl)propan-1-one
  12. 1-(3-Ethylsulfanyl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-yl)-2-morpholin-4-ium-4-ylethanone
    Compound 12 1-(3-Ethylsulfanyl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-yl)-2-morpholin-4-ium-4-ylethanone
  13. 1-Carbazol-9-yl-3-(3-methylmorpholin-4-ium-4-yl)propan-2-ol
    Compound 13 1-Carbazol-9-yl-3-(3-methylmorpholin-4-ium-4-yl)propan-2-ol
  14. N-[[(2R)-1-Ethylpyrrolidin-1-ium-2-yl]methyl]-1-(3-nitrophenyl)pyrazole-3-carboxamide
    Compound 14 N-[[(2R)-1-Ethylpyrrolidin-1-ium-2-yl]methyl]-1-(3-nitrophenyl)pyrazole-3-carboxamide
  15. 2-[(3R)-3-Ethylpiperidin-1-ium-1-yl]-1-(5-nitro-2,3-dihydroindol-1-yl)ethanone
    Compound 15 2-[(3R)-3-Ethylpiperidin-1-ium-1-yl]-1-(5-nitro-2,3-dihydroindol-1-yl)ethanone
  16. [(3R)-1-[(2-Fluoro-5-methoxyphenyl)methyl]-3-hydroxy-2-oxopiperidin-3-yl]methyl-propan-2-ylazanium
    Compound 16 [(3R)-1-[(2-Fluoro-5-methoxyphenyl)methyl]-3-hydroxy-2-oxopiperidin-3-yl]methyl-propan-2-ylazanium
  17. [3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl-[(2R)-2-hydroxy-2-phenylethyl]-methylazanium
    Compound 17 [3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl-[(2R)-2-hydroxy-2-phenylethyl]-methylazanium
  18. [(2S)-3-(4-Bromophenoxy)-2-hydroxypropyl]-[(2S)-butan-2-yl]azanium
    Compound 18 [(2S)-3-(4-Bromophenoxy)-2-hydroxypropyl]-[(2S)-butan-2-yl]azanium
  19. 1-(2,5-Dimethylmorpholin-4-ium-4-yl)-3-naphthalen-1-yloxypropan-2-ol
    Compound 19 1-(2,5-Dimethylmorpholin-4-ium-4-yl)-3-naphthalen-1-yloxypropan-2-ol
  20. [(1R)-1-(2,4-Difluorophenyl)ethyl][2-oxo-2-(3-phenyl-4,5-dihydropyrazol-1-yl)ethyl]azanium
    Compound 20 [(1R)-1-(2,4-Difluorophenyl)ethyl][2-oxo-2-(3-phenyl-4,5-dihydropyrazol-1-yl)ethyl]azanium
  21. [(1R)-1-(3-Fluorophenyl)-2-[(5-nitro-2-oxo-1,2-dihydropyridin-3-yl)formamido]ethyl]dimethylazanium
    Compound 21 [(1R)-1-(3-Fluorophenyl)-2-[(5-nitro-2-oxo-1,2-dihydropyridin-3-yl)formamido]ethyl]dimethylazanium
  22. (2-Chloro-6-fluorophenyl)methyl-[(2-pyrazol-1-ylpyridin-3-yl)methyl]azanium
    Compound 22 (2-Chloro-6-fluorophenyl)methyl-[(2-pyrazol-1-ylpyridin-3-yl)methyl]azanium
  23. [(2S)-1-Hydroxybutan-2-yl]-[(2S)-2-hydroxy-3-(2,3,5-trimethylindol-1-yl)propyl]azanium
    Compound 23 [(2S)-1-Hydroxybutan-2-yl]-[(2S)-2-hydroxy-3-(2,3,5-trimethylindol-1-yl)propyl]azanium
  24. (3-Hydroxy-6-oxobenzo[c]chromen-4-yl)methyl-[[(2R)-oxolan-2-yl]methyl]azanium
    Compound 24 (3-Hydroxy-6-oxobenzo[c]chromen-4-yl)methyl-[[(2R)-oxolan-2-yl]methyl]azanium
  25. 1,3-Benzothiazol-2-ylmethyl-[(2R)-2-hydroxy-3-phenylpropyl]-methylazanium
    Compound 25 1,3-Benzothiazol-2-ylmethyl-[(2R)-2-hydroxy-3-phenylpropyl]-methylazanium
  26. [4-(Imidazol-1-ylmethyl)phenyl]methyl-[(5-phenyl-1H-pyrazol-4-yl)methyl]azanium
    Compound 26 [4-(Imidazol-1-ylmethyl)phenyl]methyl-[(5-phenyl-1H-pyrazol-4-yl)methyl]azanium
  27. Cyclopropyl-[(1R)-1-cyclopropylethyl]-[3-(2,3-dihydroindol-1-yl)-3-oxopropyl]azanium
    Compound 27 Cyclopropyl-[(1R)-1-cyclopropylethyl]-[3-(2,3-dihydroindol-1-yl)-3-oxopropyl]azanium
  28. [(2R)-2,3-Dihydro-1,4-benzodioxin-2-yl]methyl-(quinolin-8-ylmethyl)azanium
    Compound 28 [(2R)-2,3-Dihydro-1,4-benzodioxin-2-yl]methyl-(quinolin-8-ylmethyl)azanium
  29. [(1R)-2-[(3,5-Dichlorobenzoyl)amino]-1-(furan-2-yl)ethyl]-dimethylazanium
    Compound 29 [(1R)-2-[(3,5-Dichlorobenzoyl)amino]-1-(furan-2-yl)ethyl]-dimethylazanium
  30. 1-[2-(4-Chlorophenoxy)ethyl]-N-propylpiperidin-1-ium-3-carboxamide
    Compound 30 1-[2-(4-Chlorophenoxy)ethyl]-N-propylpiperidin-1-ium-3-carboxamide
  31. Dimethyl-[2-methyl-1-[[(2R)-2-thiophen-2-ylpyrrolidine-1-carbonyl]amino]propan-2-yl]azanium
    Compound 31 Dimethyl-[2-methyl-1-[[(2R)-2-thiophen-2-ylpyrrolidine-1-carbonyl]amino]propan-2-yl]azanium
  32. [3-(2,3-Dihydroindol-1-yl)-3-oxopropyl]-ethyl-[[(2S)-oxolan-2-yl]methyl]azanium
    Compound 32 [3-(2,3-Dihydroindol-1-yl)-3-oxopropyl]-ethyl-[[(2S)-oxolan-2-yl]methyl]azanium
  33. (5,7-Dimethyl-2-oxo-1H-quinolin-3-yl)methyl-(3-morpholin-4-ylpropyl)azanium
    Compound 33 (5,7-Dimethyl-2-oxo-1H-quinolin-3-yl)methyl-(3-morpholin-4-ylpropyl)azanium
  34. (6S)-6-[(2-Hydroxy-5-nitrophenyl)methyl]-1-azabicyclo[2.2.2]octan-5-one
    Compound 34 (6S)-6-[(2-Hydroxy-5-nitrophenyl)methyl]-1-azabicyclo[2.2.2]octan-5-one
  35. [(1R)-2-[(5-Bromofuran-2-carbonyl)amino]-1-(5-methylfuran-2-yl)ethyl]-dimethylazanium
    Compound 35 [(1R)-2-[(5-Bromofuran-2-carbonyl)amino]-1-(5-methylfuran-2-yl)ethyl]-dimethylazanium
  36. 1-(2,3-Dihydroindol-1-yl)-2-[4-(2-fluorophenyl)piperazin-1-ium-1-yl]ethanone
    Compound 36 1-(2,3-Dihydroindol-1-yl)-2-[4-(2-fluorophenyl)piperazin-1-ium-1-yl]ethanone
  37. [(1R)-1-(Furan-2-yl)-2-(imidazo[1,2-a]pyridine-2-carbonylamino)ethyl]-dimethylazanium
    Compound 37 [(1R)-1-(Furan-2-yl)-2-(imidazo[1,2-a]pyridine-2-carbonylamino)ethyl]-dimethylazanium
  38. 2-(4,4-Dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl-[2-(3,5-dimethylphenoxy)ethyl]-methylazanium
    Compound 38 2-(4,4-Dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl-[2-(3,5-dimethylphenoxy)ethyl]-methylazanium
  39. [(2S)-1-Pyrazol-1-ylpropan-2-yl]-(quinolin-8-ylmethyl)azanium
    Compound 39 [(2S)-1-Pyrazol-1-ylpropan-2-yl]-(quinolin-8-ylmethyl)azanium
  40. [(1R)-1-[4-Amino-6-(dimethylamino)-1,3,5-triazin-2-yl]ethyl][2-(3,5-dimethylphenoxy)ethyl]methylazanium
    Compound 40 [(1R)-1-[4-Amino-6-(dimethylamino)-1,3,5-triazin-2-yl]ethyl][2-(3,5-dimethylphenoxy)ethyl]methylazanium
  41. (2-Pyrazol-1-ylpyridin-3-yl)methyl-(quinolin-8-ylmethyl)azanium
    Compound 41 (2-Pyrazol-1-ylpyridin-3-yl)methyl-(quinolin-8-ylmethyl)azanium
  42. 2-[4-[2-(3,5-Dimethylphenoxy)ethyl]piperazin-1-ium-1-yl]-1-pyrrolidin-1-ylethanone
    Compound 42 2-[4-[2-(3,5-Dimethylphenoxy)ethyl]piperazin-1-ium-1-yl]-1-pyrrolidin-1-ylethanone
  43. [(1R)-1-(Furan-2-yl)-2-[(6-oxo-1-propylpyridazine-3-carbonyl)amino]ethyl]-dimethylazanium
    Compound 43 [(1R)-1-(Furan-2-yl)-2-[(6-oxo-1-propylpyridazine-3-carbonyl)amino]ethyl]-dimethylazanium
  44. [(3R)-2,3-Dihydro-1,4-benzodioxin-3-yl]methyl-methyl-[2-oxo-2-(2-oxoimidazolidin-1-yl)ethyl]azanium
    Compound 44 [(3R)-2,3-Dihydro-1,4-benzodioxin-3-yl]methyl-methyl-[2-oxo-2-(2-oxoimidazolidin-1-yl)ethyl]azanium
  45. [2-(2,3-Dihydroindol-1-yl)-2-oxoethyl]-methyl-(3-phenoxypropyl)azanium
    Compound 45 [2-(2,3-Dihydroindol-1-yl)-2-oxoethyl]-methyl-(3-phenoxypropyl)azanium
  46. (2-Chlorophenyl)methyl-ethyl-[2-oxo-2-(2-oxoimidazolidin-1-yl)ethyl]azanium
    Compound 46 (2-Chlorophenyl)methyl-ethyl-[2-oxo-2-(2-oxoimidazolidin-1-yl)ethyl]azanium
  47. 3-(Furan-2-yl)-2-(4-phenethylpiperazin-4-ium-1-carbonyl)prop-2-enenitrile
    Compound 47 3-(Furan-2-yl)-2-(4-phenethylpiperazin-4-ium-1-carbonyl)prop-2-enenitrile
  48. [(1R)-2-[(3,5-Dinitrobenzoyl)amino]-1-(furan-2-yl)ethyl]-dimethylazanium
    Compound 48 [(1R)-2-[(3,5-Dinitrobenzoyl)amino]-1-(furan-2-yl)ethyl]-dimethylazanium
  49. [2-(2,6-Difluorophenyl)-2-hydroxyethyl]-[2-(3-fluorophenoxy)ethyl]-methylazanium
    Compound 49 [2-(2,6-Difluorophenyl)-2-hydroxyethyl]-[2-(3-fluorophenoxy)ethyl]-methylazanium
  50. Dimethyl-[1-[(5-methyl-1H-imidazo[1,2-a]pyridin-4-ium-2-carbonyl)amino]propan-2-yl]azanium
    Compound 50 Dimethyl-[1-[(5-methyl-1H-imidazo[1,2-a]pyridin-4-ium-2-carbonyl)amino]propan-2-yl]azanium
  51. Ethyl (3R)-1-[2-oxo-2-(2-oxoimidazolidin-1-yl)ethyl]piperidin-1-ium-3-carboxylate
    Compound 51 Ethyl (3R)-1-[2-oxo-2-(2-oxoimidazolidin-1-yl)ethyl]piperidin-1-ium-3-carboxylate
  52. [1-(Furan-2-yl)-2-[(5-methyl-1H-imidazo[1,2-a]pyridin-4-ium-2-carbonyl)amino]ethyl]-dimethylazanium
    Compound 52 [1-(Furan-2-yl)-2-[(5-methyl-1H-imidazo[1,2-a]pyridin-4-ium-2-carbonyl)amino]ethyl]-dimethylazanium
  53. [5-(3,5-Dichlorophenyl)furan-2-yl]methyl-(2-hydroxyethyl)azanium
    Compound 53 [5-(3,5-Dichlorophenyl)furan-2-yl]methyl-(2-hydroxyethyl)azanium
  54. [5-(3,5-Dichlorophenyl)furan-2-yl]methyl-(2-methoxyethyl)azanium
    Compound 54 [5-(3,5-Dichlorophenyl)furan-2-yl]methyl-(2-methoxyethyl)azanium
  55. [5-(3,5-Dichlorophenyl)furan-2-yl]methyl-methylazanium
    Compound 55 [5-(3,5-Dichlorophenyl)furan-2-yl]methyl-methylazanium
  56. [5-(3,5-Dichlorophenyl)furan-2-yl]methyl-(1-hydroxy-2-methylpropan-2-yl)azanium
    Compound 56 [5-(3,5-Dichlorophenyl)furan-2-yl]methyl-(1-hydroxy-2-methylpropan-2-yl)azanium
  57. [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-methylazanium
    Compound 57 [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-methylazanium
  58. [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-(2-hydroxyethyl)azanium
    Compound 58 [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-(2-hydroxyethyl)azanium
  59. [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-[(2S)-1-hydroxybutan-2-yl]azanium
    Compound 59 [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-[(2S)-1-hydroxybutan-2-yl]azanium
  60. [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-[(2S)-2-hydroxypropyl]azanium
    Compound 60 [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-[(2S)-2-hydroxypropyl]azanium
  61. [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-ethylazanium
    Compound 61 [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-ethylazanium
  62. [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-propan-2-ylazanium
    Compound 62 [5-(2,5-Dichlorophenyl)furan-2-yl]methyl-propan-2-ylazanium
  63. (1-Hydroxy-2-methylpropan-2-yl)-[[5-[3-(trifluoromethyl)phenyl]furan-2-yl]methyl]azanium
    Compound 63 (1-Hydroxy-2-methylpropan-2-yl)-[[5-[3-(trifluoromethyl)phenyl]furan-2-yl]methyl]azanium
  64. [5-(3-Chloro-4-fluorophenyl)furan-2-yl]methyl-(1-hydroxy-2-methylpropan-2-yl)azanium
    Compound 64 [5-(3-Chloro-4-fluorophenyl)furan-2-yl]methyl-(1-hydroxy-2-methylpropan-2-yl)azanium
  65. tert-Butyl-[(5-phenylfuran-2-yl)methyl]azanium
    Compound 65 tert-Butyl-[(5-phenylfuran-2-yl)methyl]azanium
  66. tert-Butyl-[[5-(2-chlorophenyl)furan-2-yl]methyl]azanium
    Compound 66 tert-Butyl-[[5-(2-chlorophenyl)furan-2-yl]methyl]azanium
  67. (1-Hydroxy-2-methylpropan-2-yl)-[(5-phenylfuran-2-yl)methyl]azanium
    Compound 67 (1-Hydroxy-2-methylpropan-2-yl)-[(5-phenylfuran-2-yl)methyl]azanium
  68. [5-(3-Chloro-4-methylphenyl)furan-2-yl]methyl-(1-hydroxy-2-methylpropan-2-yl)azanium
    Compound 68 [5-(3-Chloro-4-methylphenyl)furan-2-yl]methyl-(1-hydroxy-2-methylpropan-2-yl)azanium
  69. (5-Phenylfuran-2-yl)methyl-propan-2-ylazanium
    Compound 69 (5-Phenylfuran-2-yl)methyl-propan-2-ylazanium
  70. Cyclopropyl-[[5-(2,5-dichlorophenyl)furan-2-yl]methyl]azanium
    Compound 70 Cyclopropyl-[[5-(2,5-dichlorophenyl)furan-2-yl]methyl]azanium
  71. [5-(3-Chlorophenyl)furan-2-yl]methyl-[(2S)-2-hydroxypropyl]azanium
    Compound 71 [5-(3-Chlorophenyl)furan-2-yl]methyl-[(2S)-2-hydroxypropyl]azanium
  72. [5-(3-Chloro-2-methylphenyl)furan-2-yl]methyl-[(2S)-1-hydroxybutan-2-yl]azanium
    Compound 72 [5-(3-Chloro-2-methylphenyl)furan-2-yl]methyl-[(2S)-1-hydroxybutan-2-yl]azanium

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Author information

  1. These authors contributed equally to this work.

    • Jens Carlsson,
    • Ryan G Coleman &
    • Vincent Setola

Affiliations

  1. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA.

    • Jens Carlsson,
    • Ryan G Coleman,
    • John J Irwin,
    • Hao Fan,
    • Avner Schlessinger,
    • Andrej Sali &
    • Brian K Shoichet
  2. Department of Pharmacology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

    • Vincent Setola &
    • Bryan L Roth
  3. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.

    • Hao Fan,
    • Avner Schlessinger &
    • Andrej Sali
  4. California Institute for Quantitative Biosciences, University of California San Francisco, San Francisco, California, USA.

    • Hao Fan,
    • Avner Schlessinger &
    • Andrej Sali

Contributions

Docking and homology modeling was conducted by J.C. and R.G.C., the latter with assistance from H.F., A. Schlessinger and A. Sali, J.J.I. and B.K.S. assisted with compound selection and strategy, J.J.I. lent expertise with the DOCK Blaster toolchain and fixed problems with ZINC. B.L.R. and V.S. were responsible for the pharmacological guidance as to the appropriate specificity tests, while V.S. conducted all the experiments. All authors contributed to the writing of the manuscript.

Competing financial interests

The authors declare no competing financial interests.

Corresponding authors

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Supplementary information

PDF files

  1. Supplementary Text and Figures (2M)

    Supplementary Methods and Supplementary Results

Excel files

  1. Supplementary Data Set 1 (147K)

    SupplementaryDataset1.xlsx

Text files

  1. Supplementary Data Set 2 (138K)

    model_receptor.txt

  2. Supplementary Data Set 3 (20K)

    model_ligands.txt

  3. Supplementary Data Set 4 (138K)

    crystal_receptor.txt

  4. Supplementary Data Set 5 (16K)

    crystal_ligands.txt

Additional data