WO2005001645A3 - Method and computer program product for drug discovery using weighted grand canonical metropolis monte carlo sampling - Google Patents

Method and computer program product for drug discovery using weighted grand canonical metropolis monte carlo sampling Download PDF

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Publication number
WO2005001645A3
WO2005001645A3 PCT/US2004/020059 US2004020059W WO2005001645A3 WO 2005001645 A3 WO2005001645 A3 WO 2005001645A3 US 2004020059 W US2004020059 W US 2004020059W WO 2005001645 A3 WO2005001645 A3 WO 2005001645A3
Authority
WO
WIPO (PCT)
Prior art keywords
fragments
weighted
protein
monte carlo
metropolis
Prior art date
Application number
PCT/US2004/020059
Other languages
French (fr)
Other versions
WO2005001645A2 (en
Inventor
Stephan Brunner
Charles Karney
Original Assignee
Locus Pharmaceuticals Inc
Sarnoff Corp
Stephan Brunner
Charles Karney
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 Locus Pharmaceuticals Inc, Sarnoff Corp, Stephan Brunner, Charles Karney filed Critical Locus Pharmaceuticals Inc
Priority to EP04776948A priority Critical patent/EP1644860A4/en
Publication of WO2005001645A2 publication Critical patent/WO2005001645A2/en
Publication of WO2005001645A3 publication Critical patent/WO2005001645A3/en

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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

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  • 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

A method and computer program product for modeling a system that includes a protein and a plurality of different fragment types in order to identify drug leads is presented (120, 130, 140, 150). The basis of the method is a weighted Metropolis Monte Carlo approach for sampling the grand canonical ensemble. This method distinguishes itself from an energy minimization approach in that it provides fragment distributions which are consistent with thermal fluctuations at physiologically relevant temperatures. The weighted Metropolis Monte Carlo scheme performs a quasi-uniform sampling of all regions of interest on the protein, and, in this way, enables to resolve the wide range in densities of the thermodynamic distribution which could not be achieved by a non-weighted Metropolis scheme. Making use of the properties of the grand canonical ensemble, the affinity of fragments for different regions on the protein surface can be efficiently computed, using a so-called “simulated annealing of the chemical potential” process. A protein binding site is then identified as a region with high affinity for multiple fragments with a diverse set of physico-chemical properties. Within a binding site, assembly of fragments into drug leads is finally carried out based on binding affinity of the different fragments, on geometric proximity, and a variety of rules by which organic fragments may bond together.
PCT/US2004/020059 2003-06-27 2004-06-25 Method and computer program product for drug discovery using weighted grand canonical metropolis monte carlo sampling WO2005001645A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP04776948A EP1644860A4 (en) 2003-06-27 2004-06-25 Method and computer program product for drug discovery using weighted grand canonical metropolis monte carlo sampling

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US48277403P 2003-06-27 2003-06-27
US60/482,774 2003-06-27
US50927203P 2003-10-08 2003-10-08
US60/509,272 2003-10-08
US50954303P 2003-10-09 2003-10-09
US60/509,543 2003-10-09
US53168703P 2003-12-23 2003-12-23
US60/531,687 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
US10/748,708 2003-12-31
US10/794,181 2004-03-08
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

Publications (2)

Publication Number Publication Date
WO2005001645A2 WO2005001645A2 (en) 2005-01-06
WO2005001645A3 true WO2005001645A3 (en) 2005-04-28

Family

ID=33556805

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/020059 WO2005001645A2 (en) 2003-06-27 2004-06-25 Method and computer program product for drug discovery using weighted grand canonical metropolis monte carlo sampling

Country Status (2)

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

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
WO2005121947A2 (en) * 2004-06-07 2005-12-22 Locus Pharmaceuticals, Inc. Identification of ligands for macromolecules
CN100442270C (en) * 2005-08-08 2008-12-10 上海市计量测试技术研究院 Method of analog computing synthesis indeterminacy using Monte carlo acounting
WO2010090700A2 (en) * 2009-01-21 2010-08-12 President And Fellows Of Harvard College Systems and methods for generating and/or characterizing molecules for pharmaceutical and other uses
CN109932713B (en) * 2019-03-04 2021-07-09 北京旷视科技有限公司 Positioning method, positioning device, computer equipment, readable storage medium and robot

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5557535A (en) * 1993-04-28 1996-09-17 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
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
US5884230A (en) * 1993-04-28 1999-03-16 Immunex Corporation Method and system for protein modeling
US6029114A (en) * 1996-07-31 2000-02-22 Queen's University At Kingston Molecular modelling of neurotrophin-receptor binding
US6251620B1 (en) * 1995-08-30 2001-06-26 Ariad Pharmaceuticals, Inc. Three dimensional structure of a ZAP tyrosine protein kinase fragment and modeling methods
US6489608B1 (en) * 1999-04-06 2002-12-03 Micromass Limited Method of determining peptide sequences by mass spectrometry
US20030055574A1 (en) * 1996-02-15 2003-03-20 W. Clark Still Method for determining relative energies of two or more different molecules
US6640191B1 (en) * 1999-12-30 2003-10-28 The Regents Of The University Of California Library design in combinatorial chemistry by Monte Carlo methods
US6735530B1 (en) * 1998-09-23 2004-05-11 Sarnoff Corporation Computational protein probing to identify binding sites

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5557535A (en) * 1993-04-28 1996-09-17 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
US20030055574A1 (en) * 1996-02-15 2003-03-20 W. Clark Still Method for determining relative energies of two or more different molecules
US6029114A (en) * 1996-07-31 2000-02-22 Queen's University At Kingston Molecular modelling of neurotrophin-receptor binding
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
US6489608B1 (en) * 1999-04-06 2002-12-03 Micromass Limited Method of determining peptide sequences by mass spectrometry
US6640191B1 (en) * 1999-12-30 2003-10-28 The Regents Of The University Of California Library design in combinatorial chemistry by Monte Carlo methods

Also Published As

Publication number Publication date
EP1644860A2 (en) 2006-04-12
WO2005001645A2 (en) 2005-01-06
EP1644860A4 (en) 2008-08-06

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