EP1644860A4 - Procede et programme informatique permettant de decouvrir des medicaments a l'aide d'un echantillonnage de metropolis monte carlo grand-canonique pondere - Google Patents

Procede et programme informatique permettant de decouvrir des medicaments a l'aide d'un echantillonnage de metropolis monte carlo grand-canonique pondere

Info

Publication number
EP1644860A4
EP1644860A4 EP04776948A EP04776948A EP1644860A4 EP 1644860 A4 EP1644860 A4 EP 1644860A4 EP 04776948 A EP04776948 A EP 04776948A EP 04776948 A EP04776948 A EP 04776948A EP 1644860 A4 EP1644860 A4 EP 1644860A4
Authority
EP
European Patent Office
Prior art keywords
fragment
computer
fragments
protein
program code
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04776948A
Other languages
German (de)
English (en)
Other versions
EP1644860A2 (fr
Inventor
Stephan Brunner
Charles Karney
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sarnoff Corp
Locus Pharmaceuticals Inc
Original Assignee
Sarnoff Corp
Locus Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/748,708 external-priority patent/US20040267509A1/en
Priority claimed from US10/794,181 external-priority patent/US20040267456A1/en
Application filed by Sarnoff Corp, Locus Pharmaceuticals Inc filed Critical Sarnoff Corp
Publication of EP1644860A2 publication Critical patent/EP1644860A2/fr
Publication of EP1644860A4 publication Critical patent/EP1644860A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/50—Molecular design, e.g. of drugs
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
    • G16B15/30—Drug targeting using structural data; Docking or binding prediction
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C10/00—Computational theoretical chemistry, i.e. ICT specially adapted for theoretical aspects of quantum chemistry, molecular mechanics, molecular dynamics or the like

Definitions

  • the invention described herein relates to models for molecular interaction, and in particular the use of such models for drug discovery.
  • the MCSS approach for example is essentially based on an energy minimization procedure, providing fragment states corresponding to various local minima of the potential energy field representing the fragment- protein interaction.
  • Such a procedure is computationally more expeditious than computing a thermodynamic ensemble of states, but is unable to provide information on entropic effects, essential for free energy estimates.
  • the probability P(N) for having N fragments in the system is given by This is simply the Poisson distribution with parameter Z.
  • the average number of fragments in the system is given by
  • the association constant is the basic biologically relevant quantity.
  • Equations (30), (31) and (32) provide the basic relations for interpreting the WGCMMC data.
  • a first estimate of the binding affinity of a given fragment for different regions on the protein surface can be obtained by assigning a critical R c to each fragment-residue pair.
  • These B c values are obtained from the WGCMMC data by applying relation (32), and by assigning a binding volume ⁇ V& to each residue based of the following proximity criteria:
  • the Van der Walls radii are typically defined as half the Lennard-Jones parameter from the considered molecular-mechanics force-field (e.g. AMBER) used for the Monte Carlo simulation.
  • Equations (42) to (47) can naturally be generalized to various types of biased sampling, such as preferential sampling or cavity bias.
  • step 760 one may also compute the average potential energy of the clump: where E t is the potential energy of interaction of fragment i with the protein.
  • secondary memory 810 may include other means for allowing computer programs or other instructions to be loaded into computer system 800.
  • Such means may include, for example, a removable storage unit 822 and an interface 820.
  • An example of such means may include a removable memory chip (such as an EPROM, or PROM) and associated socket, or other removable storage units 822 and interfaces 820 which allow software and data to be transferred from the removable storage unit 822 to computer system 800.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physics & Mathematics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Theoretical Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biotechnology (AREA)
  • Evolutionary Biology (AREA)
  • Biophysics (AREA)
  • Medical Informatics (AREA)
  • Medicinal Chemistry (AREA)
  • Computing Systems (AREA)
  • Management, Administration, Business Operations System, And Electronic Commerce (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Cette invention concerne un procédé et un programme informatique permettant de modéliser un système comprenant une protéine et une pluralité de types de fragments différents afin d'identifier des pistes thérapeutiques. Ce procédé repose sur une approche de Métropolis Monté Carlo pondérée consistant à échantillonner l'ensemble grand-canonique. Ce procédé diffère d'une approche de minimisation énergétique en ce qu'il produit des répartitions de fragments correspondant à des fluctuations thermiques à des températures physiologiquement pertinentes. Le mécanisme de Métropolis Monté Carlo pondéré effectue un échantillonnage quasi-uniforme de toutes les régions d'intérêt sur la protéine et permet ainsi de résoudre la vaste gamme de densités de la répartition thermodynamique, ce qui ne pourrait pas être obtenu par un mécanisme de Métropolis non pondéré. L'utilisation des propriétés de l'ensemble grand-canonique permet de calculer efficacement l'affinité de fragments pour différentes régions sur la surface de la protéine à l'aide d'un procédé appelé 'recuit simulé du potentiel chimique'. Un site de liaison à une protéine est ensuite identifié comme étant une région présentant une grande affinité pour de multiples fragments présentant un ensemble diversifié de propriétés physico-chimiques. A l'intérieur d'un site de liaison, l'assemblage de fragments en pistes thérapeutiques est finalement effectué sur la base de l'affinité de liaison des différents fragments, de la proximité géométrique et d'une variété de règles selon lesquelles des fragments organiques peuvent se lier les uns aux autres.
EP04776948A 2003-06-27 2004-06-25 Procede et programme informatique permettant de decouvrir des medicaments a l'aide d'un echantillonnage de metropolis monte carlo grand-canonique pondere Withdrawn EP1644860A4 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US48277403P 2003-06-27 2003-06-27
US50927203P 2003-10-08 2003-10-08
US50954303P 2003-10-09 2003-10-09
US53168703P 2003-12-23 2003-12-23
US10/748,708 US20040267509A1 (en) 2003-06-27 2003-12-31 Method and computer program product for drug discovery using weighted Grand Canonical Metropolis Monte Carlo sampling
US10/794,181 US20040267456A1 (en) 2003-06-27 2004-03-08 Method and computer program product for drug discovery using weighted grand canonical metropolis Monte Carlo sampling
PCT/US2004/020059 WO2005001645A2 (fr) 2003-06-27 2004-06-25 Procede et programme informatique permettant de decouvrir des medicaments a l'aide d'un echantillonnage de metropolis monte carlo grand-canonique pondere

Publications (2)

Publication Number Publication Date
EP1644860A2 EP1644860A2 (fr) 2006-04-12
EP1644860A4 true EP1644860A4 (fr) 2008-08-06

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP04776948A Withdrawn EP1644860A4 (fr) 2003-06-27 2004-06-25 Procede et programme informatique permettant de decouvrir des medicaments a l'aide d'un echantillonnage de metropolis monte carlo grand-canonique pondere

Country Status (2)

Country Link
EP (1) EP1644860A4 (fr)
WO (1) WO2005001645A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7415361B2 (en) * 2003-12-09 2008-08-19 Locus Pharmaceuticals, Inc. Methods and systems for analyzing and determining ligand-residue interaction
EP1763814A4 (fr) * 2004-06-07 2008-12-10 Locus Pharmaceuticals Inc Identification de ligands pour macromolecules
CN100442270C (zh) * 2005-08-08 2008-12-10 上海市计量测试技术研究院 一种用蒙特卡罗统计模拟计算合成不确定度的方法
WO2010090700A2 (fr) * 2009-01-21 2010-08-12 President And Fellows Of Harvard College Systèmes et procédés de production et/ou de caractérisation de molécules à des fins pharmaceutiques et autres
CN109932713B (zh) * 2019-03-04 2021-07-09 北京旷视科技有限公司 定位方法、装置、计算机设备、可读存储介质和机器人

Family Cites Families (10)

* Cited by examiner, † Cited by third party
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US5453937A (en) * 1993-04-28 1995-09-26 Immunex Corporation Method and system for protein modeling
US5884230A (en) * 1993-04-28 1999-03-16 Immunex Corporation Method and system for protein modeling
US5600571A (en) * 1994-01-18 1997-02-04 The Trustees Of Columbia University In The City Of New York Method for determining protein tertiary structure
US6251620B1 (en) * 1995-08-30 2001-06-26 Ariad Pharmaceuticals, Inc. Three dimensional structure of a ZAP tyrosine protein kinase fragment and modeling methods
US6622094B2 (en) * 1996-02-15 2003-09-16 The Trustees Of Columbia University In The City Of New York Method for determining relative energies of two or more different molecules
GB9616105D0 (en) * 1996-07-31 1996-09-11 Univ Kingston TrkA binding site of NGF
US5854992A (en) * 1996-09-26 1998-12-29 President And Fellows Of Harvard College System and method for structure-based drug design that includes accurate prediction of binding free energy
US6735530B1 (en) * 1998-09-23 2004-05-11 Sarnoff Corporation Computational protein probing to identify binding sites
EP1688987A1 (fr) * 1999-04-06 2006-08-09 Micromass UK Limited Méthode pour l' identification de peptides et de protéines par spectrométrie de masse
US6640191B1 (en) * 1999-12-30 2003-10-28 The Regents Of The University Of California Library design in combinatorial chemistry by Monte Carlo methods

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CAFLISCH A ET AL: "Multiple copy simultaneous search and construction of ligands in binding sites: application to inhibitors of HIV-1 aspartic proteinase.", JOURNAL OF MEDICINAL CHEMISTRY 23 JUL 1993, vol. 36, no. 15, 23 July 1993 (1993-07-23), pages 2142 - 2167, XP002485505, ISSN: 0022-2623 *
GUARNIERI F ET AL: "SIMULATED ANNEALING OF CHEMICAL POTENTIAL: A GENERAL PROCEDURE FOR LOCATING BOUND WATERS. APPLICATION TO THE STUDY OF THE DIFFERENTIAL HYDRATION PROPENSITIES FOR THE MAJOR AND MINOR GROOVES OF DNA", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, US, vol. 118, no. 35, 1 January 1996 (1996-01-01), pages 8493/8494, XP009061246, ISSN: 0002-7863 *

Also Published As

Publication number Publication date
WO2005001645A3 (fr) 2005-04-28
WO2005001645A2 (fr) 2005-01-06
EP1644860A2 (fr) 2006-04-12

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