WO1996032642A1 - Procede de chromatographie d'affinite pour le criblage de bibliotheques combinatoires - Google Patents
Procede de chromatographie d'affinite pour le criblage de bibliotheques combinatoires Download PDFInfo
- Publication number
- WO1996032642A1 WO1996032642A1 PCT/GB1996/000790 GB9600790W WO9632642A1 WO 1996032642 A1 WO1996032642 A1 WO 1996032642A1 GB 9600790 W GB9600790 W GB 9600790W WO 9632642 A1 WO9632642 A1 WO 9632642A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- biological
- ligands
- interest
- affinity
- column
- Prior art date
Links
- 238000012216 screening Methods 0.000 title description 2
- 238000004587 chromatography analysis Methods 0.000 title 1
- 239000003446 ligand Substances 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000011159 matrix material Substances 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 239000007790 solid phase Substances 0.000 claims abstract description 12
- 238000003556 assay Methods 0.000 claims abstract description 9
- 230000014759 maintenance of location Effects 0.000 claims abstract description 4
- 239000012634 fragment Substances 0.000 claims description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 4
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 238000004949 mass spectrometry Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 8
- 230000000717 retained effect Effects 0.000 description 7
- 238000001042 affinity chromatography Methods 0.000 description 6
- 229920002521 macromolecule Polymers 0.000 description 6
- 230000027455 binding Effects 0.000 description 5
- YJQPYGGHQPGBLI-KGSXXDOSSA-N novobiocin Chemical class O1C(C)(C)[C@H](OC)[C@@H](OC(N)=O)[C@@H](O)[C@@H]1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-KGSXXDOSSA-N 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YJQPYGGHQPGBLI-UHFFFAOYSA-N Novobiocin Natural products O1C(C)(C)C(OC)C(OC(N)=O)C(O)C1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000002118 epoxides Chemical class 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229960002950 novobiocin Drugs 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 108010054814 DNA Gyrase Proteins 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- 108010067902 Peptide Library Proteins 0.000 description 2
- 238000003314 affinity selection Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229940124606 potential therapeutic agent Drugs 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000013627 low molecular weight specie Substances 0.000 description 1
- 150000007974 melamines Chemical class 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- -1 small molecule compounds Chemical class 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/536—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase
- G01N33/537—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase with separation of immune complex from unbound antigen or antibody
- G01N33/538—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase with separation of immune complex from unbound antigen or antibody by sorbent column, particles or resin strip, i.e. sorbent materials
Definitions
- the invention relates to methods for determining the affinity of chemical compounds for a biological of interest under physiologically relevant conditions.
- the invention relates to the deconvolution of library mixtures of chemical compounds.
- a fragment of the DNA gyrase enzyme may be immobilised on the stationary phase of a high performance liquid chromatography column and successfully used to assay the affinity of novobiocin analogues for the DNA gyrase enzyme. Therefore in a first aspect of the present invention we provide an assay method for determining the affinity of low molecular weight ligands for a biological of interest, which method comprises immobilising the biological of interest on a solid phase matrix, contacting this with a mixture comprising the ligands, removing any unbound ligands from the matrix, eluting the ligands from the matrix and establishing their affinity for the biological of interest by reference to their order of retention on the column.
- the biological of interest may be a peptide macromolecule or a synthetic or otherwise modified variant thereof.
- a particular advantage of the method of the invention is that the identity, structure and/or function of the chosen macromolecule is not critical to the performance of the invention. It need not be structurally or functionally intact. It will be understood that the biological of interest may be attached to the solid phase matrix in a number of different ways to identify different ligands for different epitopes.
- the biological of interest may have itself been isolated by its affinity, for example by affinity chromatography, for a known ligand whose properties, for example binding affinity, it is desired to imitate. It may be a fragment of a larger macromolecule; such fragments may lack the biochemical function of larger macromolecule(s) from which they are derived. In a particular aspect of the invention the biological of interest is an enzyme fragment.
- the ligands are low molecular weight species to which antibodies cannot be readily raised. As such they may have a molecular weight of less than about 2000 daltons. In particular they have a molecular wieght of less than about 1200 daltons. More particularly the ligands have a molecular weight of less than about 1000 daltons, such as less than 800, 600, 400 or 200 daltons. They may be extracts of natural products, optionally chemically modified; alternatively they may be extracts of a synthetic product or products optionally metabolically modified. They may also be mixtures of peptides, such as peptide libraries, to which antibodies cannot readily be raised.
- the low molecular weight ligands are potential drug candidates, ie. synthetic small molecule compounds prepared as mixtures, for example as combinatorial libraries, or mixtures prepared from separate optionally purified single compounds. Any convenient number of ligands may be present in the mixture, such as up to 5,10, 20, 30, 40, 50, 100, 200, 400, 1000 or up to 10,000 ligands..
- the low molecular weight ligand is not a specific ligand or partner for the biological of interest as would be the case for example with antibodies and corresponding antigens.
- the solid phase matrix is conveniently a column, such as an epoxide based column, to which the biological of interest has been bound.
- the ligand containing mixture is passed through the column any convenient number of times, such as once, twice, or thrice.
- Ligand(s) which show affinity for the biological of interest are retained on the column whereas those with negligible affinity are not retained and are washed off the column.
- the biological of interest is covalently bound to the solid phase, for instance using reactive side chains on the accessible surface of the biological of interest and the solid phase.
- Suitable materials and methods are set out, for example in "Affinity Chromatography, principles and methods", published by Pharmacia Fine Chemicals.
- the solid phase may be activated to provide points of attachment such as epoxides or it may have intrinsically reactive surface functional groups such as carboxyl. It will be understood that the biological of interest will not normally be bound at a specific point of attachment but rather at one of a number of possible alternatives. If necessary a ligand binding site may be preserved by a known ligand during attachment of the biological of interest to the solid phase. Alternatively specific binding interactions may be used, for example biotin/avidin are used as the interface between the solid phase matrix and the biological of interest.
- the retained ligands are then eluted and retained, preferably as ordered fractions for further analysis.
- a particular advantage of the methods of the present invention is that ligands are contacted with the biological of interest under physiologically relevant conditions (pH, temperature, salt concentrations and the like, all as found in the human or animal body). There is no application, for example of electric current or field, which could affect the interaction between ligands and the biological of interest, as would be the case in affinity gel electrophoresis.
- the retained ligands are trapped on one or more high performance liquid chromatography (hplc) columns. This facilitates their further analysis. Suitable trapping columns will be apparent to the scientist of ordinary skill, and include C18 reverse phase HPLC cartridge columns.
- the retained ligands are eluted from the one or more hplc columns (after optional backflushing) into a mass spectrometer such as an electrospray mass spectrometer.
- a mass spectrometer such as an electrospray mass spectrometer.
- the solid phase matrix retains the biological of interest and it is not generally necessary to add further material to the column.
- the method of the invention may be used to rank the relative affinity either singly or in admixture of a series of compounds (ligands) for the biological of interest; alternatively the method may be calibrated to give a measure of the absolute affinity of each of a series of ligands for the biological of interest.
- ligands are of use pei s_e_ and also as starting points for the design of related ligands.
- the biological of interest may have itself been isolated by its affinity, for example by affinity chromatography, for a known ligand whose properties, for example binding affinity, it is desired to imitate. Therefore, in a further aspect of the invention the biological of interest is firstly isolated by its affinity for a known ligand, such as a small molecule drug.
- a known ligand such as a small molecule drug.
- the ligands identified by the methods of the invention are functional analogues of the known ligand.
- This is used as a template to "print" functional analogues of the known ligand.
- Such analogues may be of diverse chemical structure.
- ligands have -uses as biochemical tools, as diagnostic and analytical agents, and in particular as pharmaceutical and agrochemical agents.
- Such ligands may for example be potential therapeutic agents or metabolites of such agents.
- they are preferably chemical compounds of low molecular weight and potential therapeutic agents. They are for example of less than about 1000 daltons, such as less than 800, 600 or 400 daltons.
- An affinity column was made by filling an epoxide based column (Hydropore EP 12 micron - Rainin, catalogue no. 83-A03-GTI) with a dialysed sample of the 24kD N-terminal 2-220 amino acid residue fragment of the gyrase B subunit, which had itself been prepared by affinity chromatography on novobiocin-sepharose by the method of Gilbert and Maxwell (E.J. Gilbert and A. Maxwell, Molecular Microbiology, 1994, 12, 365-374). After standing for 12 hours the column was washed with buffer (0.1M mixed potassium phosphate pH7) and shown to act as an affinity column for compounds binding to this protein by testing with novobiocin (E. J. Gilbert and A.
- Maxwell, op cit Maxwell, op cit analogues which in a gyrase assay had IC50 values in the range from lug/mL to greater than 400ug/mL.
- the gyrase assay procedure used was analogous to that disclosed by Gellert et al (Proc.Natl.Acad.Sci.USA, 1976, 21, 3872-3876).
- the order of retention on the column was found to be equal to the order of enzyme inhibition.
- One novobiocin analogue which has an enzyme inhibitory potency of approximately one tenth that of novobiocin was retained by between 4-10 column volumes beyond the void volume.
- the affinity of this compound for the corresponding gyrase 24 kD fragment in solution was measured as -10- and the gyrase inhibitory potency was 1.6 ug/mL.
- the column Having thus shown that the column behaved reproducibly as an affinity column and that this behaviour was consistent even in the presence of a 50 fold excess of a non-binding novobiocin structural analogue with negligible gyrase inhibitory activity, the column was used to examine three library mixtures each comprising nine differently substituted triaminotriazines. Using liquid chromatography (Hewlett-Packard 1050, uv detection at 305 nanometres) it was possible to identify which of the three libraries contained the active components by the tailing of the HPLC trace.
- Hewlett-Packard 1050 Hewlett-Packard 1050, uv detection at 305 nanometres
- This library was passed through the column a second time and the fraction whose elution time corresponded to the most strongly bound components passed directly through a short Cl 8 column (Hewlett-Packard, cartridge ODS Hypersil 5 micron 20x4mm) to trap these components.
- This trap was then connected directly to the probe of an electrospray spectrometer (BioQ spectrometer Vacuum Generators Biotechnology - Fisons Instruments) and backflushed with acetonitrile/water (50:50) 0.5% formic acid.
- the eluent was continuously monitored by mass spectrometry and after about 5 minutes a broad peak was detected on the total ion trace which clearly showed the presence of two major components.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Food Science & Technology (AREA)
- Biochemistry (AREA)
- Cell Biology (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Microbiology (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Procédé de détermination permettant de déterminer l'affinité de ligands de faible poids molaire pour une substance biologique recherchée dans des conditions appropriées du point de vue physiologique. Ce procédé consiste à immobiliser la substance biologique recherchée sur une matrice à phase solide, à mettre en contact cette dernière avec un mélange comprenant les ligands, à éliminer de la matrice les ligands non liés, à éluer les ligands de la matrice puis à établir leur affinité pour la substance biologique recherchée en fonction de leur ordre de rétention dans la colonne.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8530797A JPH11503526A (ja) | 1995-04-08 | 1996-04-01 | コンビナトリアルライブラリーをスクリーニングするためのアフィニティークロマトグラフィー法 |
| EP96908266A EP0820591A1 (fr) | 1995-04-08 | 1996-04-01 | Procede de chromatographie d'affinite pour le criblage de bibliotheques combinatoires |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9507366.4A GB9507366D0 (en) | 1995-04-08 | 1995-04-08 | Assay |
| GB9507366.4 | 1995-04-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996032642A1 true WO1996032642A1 (fr) | 1996-10-17 |
Family
ID=10772806
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1996/000790 WO1996032642A1 (fr) | 1995-04-08 | 1996-04-01 | Procede de chromatographie d'affinite pour le criblage de bibliotheques combinatoires |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0820591A1 (fr) |
| JP (1) | JPH11503526A (fr) |
| GB (2) | GB9507366D0 (fr) |
| WO (1) | WO1996032642A1 (fr) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6054047A (en) * | 1998-03-27 | 2000-04-25 | Synsorb Biotech, Inc. | Apparatus for screening compound libraries |
| JP2002501176A (ja) * | 1998-01-08 | 2002-01-15 | ザ・ユニヴァーシティ・オヴ・リヴァプール | 蛋白質親和性リガンド同定へのマスフィンガープリンティングの利用 |
| US6607921B1 (en) | 1998-03-27 | 2003-08-19 | Ole Hindsgaul | Methods for screening compound libraries |
| US6613575B1 (en) | 1998-03-27 | 2003-09-02 | Ole Hindsgaul | Methods for screening compound libraries |
| US6627453B1 (en) | 1998-03-27 | 2003-09-30 | Ole Hindsgaul | Methods for screening compound libraries |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997043301A2 (fr) * | 1996-05-10 | 1997-11-20 | Novartis Ag | Identification de membres de bibliotheques combinatoires par spectrometrie de masse |
| AU774776B2 (en) * | 1999-04-15 | 2004-07-08 | University Of Virginia Patent Foundation | Proteome mining |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991019818A1 (fr) * | 1990-06-20 | 1991-12-26 | Affymax Technologies N.V. | Banque de peptides et systemes de triage |
| WO1994028424A1 (fr) * | 1993-05-28 | 1994-12-08 | Chiron Corporation | Procede de selection de sequences de peptides biologiquement actifs |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9206291D0 (en) * | 1992-03-23 | 1992-05-06 | Cancer Res Campaign Tech | Oligosaccharides having growth factor binding affinity |
-
1995
- 1995-04-08 GB GBGB9507366.4A patent/GB9507366D0/en active Pending
-
1996
- 1996-04-01 EP EP96908266A patent/EP0820591A1/fr not_active Withdrawn
- 1996-04-01 WO PCT/GB1996/000790 patent/WO1996032642A1/fr not_active Application Discontinuation
- 1996-04-01 GB GB9606887A patent/GB2300260B/en not_active Expired - Fee Related
- 1996-04-01 JP JP8530797A patent/JPH11503526A/ja active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991019818A1 (fr) * | 1990-06-20 | 1991-12-26 | Affymax Technologies N.V. | Banque de peptides et systemes de triage |
| WO1994028424A1 (fr) * | 1993-05-28 | 1994-12-08 | Chiron Corporation | Procede de selection de sequences de peptides biologiquement actifs |
Non-Patent Citations (3)
| Title |
|---|
| RONALD N. ZUCKERMANN: "Identification of highest-affinity ligands by affinity selection from equimolar peptide mixtures generated by robotic synthesis", PROC. NATL. ACAD. SCI. USA, vol. 89, May 1992 (1992-05-01), pages 4505 - 4509, XP002010943 * |
| SONGYANG, Z.: "SH2 domains recognize specific phosphopeptide sequences", CELL, vol. 72, March 1993 (1993-03-01), pages 767 - 778, XP002010941 * |
| T. FERENCI: "Genetic manipulation of bacterial surfaces through affinity chromatographic selection.", TIBS, February 1984 (1984-02-01), AMSTERDAM, pages 44 - 48, XP002010942 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002501176A (ja) * | 1998-01-08 | 2002-01-15 | ザ・ユニヴァーシティ・オヴ・リヴァプール | 蛋白質親和性リガンド同定へのマスフィンガープリンティングの利用 |
| US6054047A (en) * | 1998-03-27 | 2000-04-25 | Synsorb Biotech, Inc. | Apparatus for screening compound libraries |
| US6355163B2 (en) | 1998-03-27 | 2002-03-12 | Ole Hindsgaul | Apparatus for screening compound libraries |
| US6387257B1 (en) | 1998-03-27 | 2002-05-14 | Ole Hindsgaul | Apparatus for screening compound libraries |
| US6395169B1 (en) | 1998-03-27 | 2002-05-28 | Ole Hindgual | Apparatus for screening compound libraries |
| US6607921B1 (en) | 1998-03-27 | 2003-08-19 | Ole Hindsgaul | Methods for screening compound libraries |
| US6613575B1 (en) | 1998-03-27 | 2003-09-02 | Ole Hindsgaul | Methods for screening compound libraries |
| US6627453B1 (en) | 1998-03-27 | 2003-09-30 | Ole Hindsgaul | Methods for screening compound libraries |
| US6649415B1 (en) | 1998-03-27 | 2003-11-18 | Ole Hindsgaul | Methods for screening compound libraries |
| US6656739B2 (en) | 1998-03-27 | 2003-12-02 | Ole Hindsgaul | Methods for screening compound libraries |
| US6720190B1 (en) | 1998-03-27 | 2004-04-13 | Ole Hindsgaul | Methods for screening compound libraries |
| US6723235B2 (en) | 1998-03-27 | 2004-04-20 | Ole Hindsgaul | Apparatus for screening compound libraries |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2300260B (en) | 1998-03-11 |
| JPH11503526A (ja) | 1999-03-26 |
| GB9606887D0 (en) | 1996-06-05 |
| EP0820591A1 (fr) | 1998-01-28 |
| GB2300260A (en) | 1996-10-30 |
| GB9507366D0 (en) | 1995-05-31 |
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