WO1996030849B1 - Determination d'une structure pharmacophore au moyen d'un procede de monte carlo par consensus et biais de configuration - Google Patents
Determination d'une structure pharmacophore au moyen d'un procede de monte carlo par consensus et biais de configurationInfo
- Publication number
- WO1996030849B1 WO1996030849B1 PCT/US1996/004229 US9604229W WO9630849B1 WO 1996030849 B1 WO1996030849 B1 WO 1996030849B1 US 9604229 W US9604229 W US 9604229W WO 9630849 B1 WO9630849 B1 WO 9630849B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- compounds
- conformational
- pharmacophore
- structures
- Prior art date
Links
- 238000000342 Monte Carlo simulation Methods 0.000 title claims abstract 6
- 238000000034 method Methods 0.000 claims abstract 92
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract 42
- 238000005481 NMR spectroscopy Methods 0.000 claims abstract 10
- 239000003814 drug Substances 0.000 claims abstract 9
- 229940079593 drug Drugs 0.000 claims abstract 9
- 150000002611 lead compounds Chemical class 0.000 claims abstract 9
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract 6
- 238000004351 rotational echo double resonance Methods 0.000 claims abstract 4
- 238000012216 screening Methods 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims 146
- 230000004075 alteration Effects 0.000 claims 24
- 230000002153 concerted effect Effects 0.000 claims 16
- 238000012935 Averaging Methods 0.000 claims 12
- 239000000126 substance Substances 0.000 claims 12
- 239000000758 substrate Substances 0.000 claims 11
- 230000003993 interaction Effects 0.000 claims 9
- 239000000203 mixture Substances 0.000 claims 9
- 238000005259 measurement Methods 0.000 claims 7
- 102000037865 fusion proteins Human genes 0.000 claims 6
- 108020001507 fusion proteins Proteins 0.000 claims 6
- 230000005284 excitation Effects 0.000 claims 4
- 230000006698 induction Effects 0.000 claims 4
- 230000004913 activation Effects 0.000 claims 2
- 239000011324 bead Substances 0.000 claims 2
- 230000001934 delay Effects 0.000 claims 2
- -1 divinylbenzyl Chemical group 0.000 claims 2
- 230000000694 effects Effects 0.000 claims 2
- 230000006870 function Effects 0.000 claims 2
- 239000011521 glass Substances 0.000 claims 2
- 239000012071 phase Substances 0.000 claims 2
- 230000010399 physical interaction Effects 0.000 claims 2
- 229920005990 polystyrene resin Polymers 0.000 claims 2
- 239000011148 porous material Substances 0.000 claims 2
- 229920005989 resin Polymers 0.000 claims 2
- 239000011347 resin Substances 0.000 claims 2
- 238000009987 spinning Methods 0.000 claims 2
- LEVWYRKDKASIDU-IMJSIDKUSA-N cystine group Chemical group C([C@@H](C(=O)O)N)SSC[C@@H](C(=O)O)N LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 claims 1
- 238000012248 genetic selection Methods 0.000 claims 1
- 239000007791 liquid phase Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000004048 modification Effects 0.000 claims 1
- 238000012986 modification Methods 0.000 claims 1
- 239000012299 nitrogen atmosphere Substances 0.000 claims 1
- 238000002823 phage display Methods 0.000 claims 1
- 210000002729 polyribosome Anatomy 0.000 claims 1
- 230000010076 replication Effects 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 239000007790 solid phase Substances 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 230000002103 transcriptional effect Effects 0.000 claims 1
- 238000009509 drug development Methods 0.000 abstract 1
Abstract
Dans un mode de réalisation spécifique, l'invention concerne un procédé de sélection de composés principaux extrêmement ciblés afin de créer un médicament se fixant à une molécule cible. Ce procédé consiste à cribler une banque de diversités contre la molécule cible afin de recueillir les éléments de fixation sélective. On examine ensuite la structure des éléments sélectionnés et on détermine un candidat pharmacophore responsable de la fixation à la molécule cible. On détermine ensuite, de préférence, par résonance magnétique nucléaire REDOR, plusieurs distances interatomiques extrêmement précises dans certains des éléments sélectionnés en relation avec le candidat pharmacophore. On effectue une détermination de la structure du candidat pharmacophore au moyen d'un procédé de Monte Carlo par consensus extrêmement précis et biais de configuration, en utilisant la structure des éléments sélectionnés et en incorporant en tant que contraintes le candidat pharmacophore partagé et les distances mesurées. Cette détermination est conçue pour examiner efficacement uniquement des configurations à énergie relativement basse tout en respectant toutes contraintes structurelles présentes dans la banque de diversités organiques. Si la banque de diversités contient des peptides courts, la détermination respecte les degrés connus de liberté des peptides ainsi que toutes contraintes internes, telles que celles qui sont imposées par des ponts disulfure. Enfin, on utilise le pharmacophore extrêmement précis déterminé de cette façon, afin de sélectionner des composés organiques principaux pour créer un médicament ciblé au niveau de la molécule cible initiale.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP96909882A EP0826182A1 (fr) | 1995-03-31 | 1996-03-27 | Determination d'une structure pharmacophore au moyen d'un procede de monte carlo par consensus et biais de configuration |
| AU53246/96A AU5324696A (en) | 1995-03-31 | 1996-03-27 | Consensus configurational bias monte carlo method and system for pharmacophore structure determination |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US418,992 | 1995-03-31 | ||
| US08/418,992 US6341256B1 (en) | 1995-03-31 | 1995-03-31 | Consensus configurational bias Monte Carlo method and system for pharmacophore structure determination |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1996030849A1 WO1996030849A1 (fr) | 1996-10-03 |
| WO1996030849B1 true WO1996030849B1 (fr) | 1996-11-14 |
Family
ID=23660352
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1996/004229 WO1996030849A1 (fr) | 1995-03-31 | 1996-03-27 | Determination d'une structure pharmacophore au moyen d'un procede de monte carlo par consensus et biais de configuration |
Country Status (5)
| Country | Link |
|---|---|
| US (2) | US6341256B1 (fr) |
| EP (1) | EP0826182A1 (fr) |
| AU (1) | AU5324696A (fr) |
| CA (1) | CA2216994A1 (fr) |
| WO (1) | WO1996030849A1 (fr) |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0905512A1 (fr) * | 1997-09-25 | 1999-03-31 | Cerep | Méthode pour l'identification des structures de base ou composés actifs |
| US6168913B1 (en) * | 1997-10-14 | 2001-01-02 | Abbott Laboratories | Coding combinatorial libraries with fluorine tags |
| US6990221B2 (en) * | 1998-02-07 | 2006-01-24 | Biodiscovery, Inc. | Automated DNA array image segmentation and analysis |
| US20050112607A1 (en) * | 1999-01-23 | 2005-05-26 | Bamdad Cynthia C. | Rapid and sensitive detection of protein aggregation |
| PT1144607E (pt) * | 1999-07-20 | 2009-04-22 | Morphosys Ag | Novos métodos para apresentar (poli)peptídeos/ proteínas em partículas bacteriofágicas através de ligações dissulfureto |
| US6764858B2 (en) | 1999-09-29 | 2004-07-20 | Pharmacia & Upjohn Company | Methods for creating a compound library |
| US6677160B1 (en) | 1999-09-29 | 2004-01-13 | Pharmacia & Upjohn Company | Methods for creating a compound library and identifying lead chemical templates and ligands for target molecules |
| US7099502B2 (en) * | 1999-10-12 | 2006-08-29 | Biodiscovery, Inc. | System and method for automatically processing microarrays |
| ATE455304T1 (de) * | 2000-04-14 | 2010-01-15 | Genencor Int | Verfahren zur selektiven zielen |
| EP1337958A2 (fr) * | 2000-11-02 | 2003-08-27 | Protein Mechanics, Inc. | Procede d'auto-validation de modelage moleculaire |
| JP2005502099A (ja) * | 2001-03-12 | 2005-01-20 | ボード オブ レジェンツ，ザ ユニバーシティー オブ テキサス システム | タンパク質医薬品デザインのためのアンサンブルベースのストラテジー |
| US20030068651A1 (en) * | 2001-03-12 | 2003-04-10 | Cheryl Arrowsmith | Multi-target analysis of gene families for chemistry of high affinity and selective small molecules and other therapeutics |
| WO2003038442A2 (fr) * | 2001-10-29 | 2003-05-08 | Vertex Pharmaceuticals Incorporated | Procede de production de pharmacophores optimises |
| US20030139907A1 (en) * | 2002-01-24 | 2003-07-24 | Mccarthy Robert J | System, Method, and Product for Nanoscale Modeling, Analysis, Simulation, and Synthesis (NMASS) |
| WO2003072596A2 (fr) * | 2002-02-27 | 2003-09-04 | Protein Mechanics, Inc. | Groupage de variants conformationels de molecules, et methodes d'utilisation associees |
| US20030171873A1 (en) * | 2002-03-05 | 2003-09-11 | Bruce Hoff | Method and apparatus for grouping proteomic and genomic samples |
| AU2003220559A1 (en) * | 2002-03-26 | 2003-10-13 | Carnegie Mellon University | Methods and systems for molecular modeling |
| US20050181464A1 (en) * | 2002-04-04 | 2005-08-18 | Affinium Pharmaceuticals, Inc. | Novel purified polypeptides from bacteria |
| US20060089808A1 (en) * | 2002-07-01 | 2006-04-27 | Agrafiotis Dimitris K | Conformational sampling by self-organization |
| US7512496B2 (en) * | 2002-09-25 | 2009-03-31 | Soheil Shams | Apparatus, method, and computer program product for determining confidence measures and combined confidence measures for assessing the quality of microarrays |
| US20040267456A1 (en) * | 2003-06-27 | 2004-12-30 | Stephan Brunner | Method and computer program product for drug discovery using weighted grand canonical metropolis Monte Carlo sampling |
| US7415361B2 (en) * | 2003-12-09 | 2008-08-19 | Locus Pharmaceuticals, Inc. | Methods and systems for analyzing and determining ligand-residue interaction |
| US20050177318A1 (en) * | 2004-02-10 | 2005-08-11 | National Institute Of Statistical Sciences | Methods, systems and computer program products for identifying pharmacophores in molecules using inferred conformations and inferred feature importance |
| US20050222776A1 (en) * | 2004-03-31 | 2005-10-06 | Locus Pharmaceuticals, Inc. | Method for fragment preparation |
| WO2009024593A1 (fr) * | 2007-08-21 | 2009-02-26 | Morphosys Ag | Procédés améliorés permettant la formation de liaisons disulfure |
| GB0816100D0 (en) * | 2008-09-04 | 2008-10-15 | Univ Bristol | Molecular structure determination from nmr spectroscopy |
| US9568574B2 (en) * | 2012-03-12 | 2017-02-14 | Bruker Biospin Corporation | Pulse sequence for homonuclear J-decoupling during NMR data acquisition |
| CN102930152B (zh) * | 2012-10-26 | 2016-08-03 | 中国科学院上海药物研究所 | 一种模拟配体分子与靶标受体反应并计算预测该反应的热力学与动力学参数的方法和系统 |
| WO2014204990A2 (fr) * | 2013-06-18 | 2014-12-24 | The George Washington University, A Congressionally Chartered Not-For-Profit Corporation | Procédés de prédiction de propriétés chimiques d'après des données spectroscopiques |
| DE102014202649B4 (de) * | 2014-02-13 | 2015-12-10 | Siemens Aktiengesellschaft | Leise MR-Bildgebung durch eine variable Anzahl von Pulssequenzabschnitten zwischen zwei Vorpulsen |
| US10426424B2 (en) | 2017-11-21 | 2019-10-01 | General Electric Company | System and method for generating and performing imaging protocol simulations |
| CN112461881B (zh) * | 2020-10-16 | 2022-02-18 | 北京大学 | 一种检测rna中弱稳定性碱基对的固体核磁共振方法 |
| CN117347415B (zh) * | 2023-09-22 | 2024-10-01 | 江苏国源先进仪器技术研究院有限公司 | 一种基于高场核磁共振技术鉴定多肽药物二硫键的方法 |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225533A (en) | 1988-05-02 | 1993-07-06 | The Regents Of The University Of California | General method for producing and selecting peptides with specific properties |
| US5025388A (en) | 1988-08-26 | 1991-06-18 | Cramer Richard D Iii | Comparative molecular field analysis (CoMFA) |
| ATE168416T1 (de) | 1989-10-05 | 1998-08-15 | Optein Inc | Zellfreie synthese und isolierung von genen und polypeptiden |
| US5252743A (en) | 1989-11-13 | 1993-10-12 | Affymax Technologies N.V. | Spatially-addressable immobilization of anti-ligands on surfaces |
| JPH05503691A (ja) * | 1989-12-29 | 1993-06-17 | ユニバーシティ・テクノロジーズ・インターナショナル・インコーポレイテッド | アゴニストおよびアンタゴニストを含む生物学的に活性なリガンドの３次構造モデルの設計方法およびアンギオテンシンに基づいた新規合成アンタゴニスト |
| US5747334A (en) | 1990-02-15 | 1998-05-05 | The University Of North Carolina At Chapel Hill | Random peptide library |
| US5265030A (en) * | 1990-04-24 | 1993-11-23 | Scripps Clinic And Research Foundation | System and method for determining three-dimensional structures of proteins |
| US5331573A (en) | 1990-12-14 | 1994-07-19 | Balaji Vitukudi N | Method of design of compounds that mimic conformational features of selected peptides |
| US5270170A (en) | 1991-10-16 | 1993-12-14 | Affymax Technologies N.V. | Peptide library and screening method |
| US5348867A (en) | 1991-11-15 | 1994-09-20 | George Georgiou | Expression of proteins on bacterial surface |
| US5241470A (en) | 1992-01-21 | 1993-08-31 | The Board Of Trustees Of The Leland Stanford University | Prediction of protein side-chain conformation by packing optimization |
| WO1993017032A1 (fr) | 1992-02-24 | 1993-09-02 | The Trustees Of The University Of Pennsylvania | Techniques et intermediaires de preparation de peptidomimetismes non peptidiques |
| US5573905A (en) | 1992-03-30 | 1996-11-12 | The Scripps Research Institute | Encoded combinatorial chemical libraries |
| US5434796A (en) * | 1993-06-30 | 1995-07-18 | Daylight Chemical Information Systems, Inc. | Method and apparatus for designing molecules with desired properties by evolving successive populations |
| US5740072A (en) * | 1994-10-07 | 1998-04-14 | The Trustees Of Columbia Universuty In The City Of New York | Rapidly convergent method for boltzmann-weighted ensemble generation in free energy simulations |
| US5680319A (en) * | 1995-05-25 | 1997-10-21 | The Johns Hopkins University School Of Medicine | Hierarchical protein folding prediction |
-
1995
- 1995-03-31 US US08/418,992 patent/US6341256B1/en not_active Expired - Fee Related
-
1996
- 1996-03-27 AU AU53246/96A patent/AU5324696A/en not_active Abandoned
- 1996-03-27 WO PCT/US1996/004229 patent/WO1996030849A1/fr active Search and Examination
- 1996-03-27 CA CA002216994A patent/CA2216994A1/fr not_active Abandoned
- 1996-03-27 EP EP96909882A patent/EP0826182A1/fr not_active Withdrawn
- 1996-07-11 US US08/678,735 patent/US6150179A/en not_active Expired - Fee Related
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