Development of the Movable Type free energy method for ligand placement in X-ray crystallography
Development of the Movable Type free energy method for ligand placement in X-ray crystallography
批准号:
9347830
负责人:
Lance M Westerhoff
金额:
$16.59万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-04-01 至 2017-11-30
关键词:
Active SitesAddressAgreementAlgorithmsBindingBinding ProteinsBinding SitesBiochemistryBiologicalChemistryComplexComputational BiologyComputer softwareCrystallizationDatabasesDevelopmentDimensionsDiseaseDockingDrug DesignDrug TargetingFree EnergyHandImageryInterventionIridiumLeadLettersLibrariesLifeLigand BindingLigandsLocationManualsManuscriptsMapsMeasuresMechanicsMedicineMethodologyMethodsModelingModernizationMolecular ConformationOnline SystemsPharmacologic SubstancePhasePlayPopulationPositioning AttributePreparationPrintingProbabilityProceduresProcessProductivityProteinsProtomerPublishingQuantum MechanicsR-factorRadialReportingResearchResolutionRoentgen RaysRoleSamplingScientistSolventsStatistical MechanicsStructureSurfaceSystemTechniquesTechnologyTimeValidationWorkX-Ray Crystallographybasecloud platformcomputer programdensitydesigndrug candidatedrug discoveryelectron densityexperimental studygraphical user interfaceinnovationinsightinterestintermolecular interactionknowledge basemodel buildingnext generationnovelprotein complexprotein structurequantumreceptorresistance factorsrestraintsmall moleculesuccesstautomerthree dimensional structuretool
中文摘要
摘要
英文摘要
Abstract
The study of protein/ligand binding is one of the central problems in computational biology because of its
importance in understanding intermolecular interactions, and because of its practical payoff in drug discovery
efforts. The transformative impact accurate target/ligand structure can have in the design of next generation
medicines cannot be overstated. If we could routinely and accurately design molecules using these
approaches it would revolutionize drug discovery by winnowing out compounds with no activity while focusing
more effort and scrutiny on highly active compounds. Determining the structure of a small molecule (drug
candidate or lead compound) bound to a biological receptor (protein implicated in disease) is a necessary step
in this approach to drug discovery. X-ray techniques provide astounding insights into the structure of protein-
ligand complexes, but can be hampered by the resolution to which a crystal diffracts and the refinement
process can be hampered by the lack of good potentials for novel small molecule compounds. We have
extended our linear-scaling semiempirical quantum mechanical (QM) X-ray refinement approach and applied it
to this field with great success. This approach has proven itself to be robust enough for routine QM-based X-
ray refinement and it is currently being successfully marketed. However, since refinement methods are
ultimately built on optimization algorithms and do not include sampling, they all suffer from what is termed a
“limited radius of convergence.” Therefore, crystallographic workflows - automatic and manual - include ligand
placement as part of the model building process. Conventional automatic procedures for ligand placement are
resolution dependent and are unable to take into account the chemistry of the active site. Further, the ligand
conformation is often so highly strained that X-ray refinement alone, is unable to deduce the proper structure.
When this happens, significant intervention on the part of the crystallographer is required, which increases
expense and decreases productivity.
In this proposal we describe a novel method we call Movable Type (MT), which addresses the protein ligand
binding and scoring problem using fundamental statistical mechanics combined with a novel way to generate
the ensemble of a ligand in a protein binding pocket. Via a rapid assembly of the necessary partition functions
we directly obtain binding free energies and the low free energy poses. Conceptually, the MT method is
analogous to block and type set printing, which allows us to efficiently evaluate partition functions describing
regions or systems of interest. In this approach we construct two databases that 1) describe the probability of
certain pairwise interactions as a function of r obtained from a knowledge base (Protein Databank (PDB) or the
Cambridge Structural Database (CSD)) and 2) the energetics of the pairwise interactions as a function of r
obtained from empirical potentials, which can be either derived from the probabilities or can utilize extant
pairwise potentials like AMBER. Overall, the MT method is a general one and can use a broad range of two-
body potential functions and can be extended to higher-order interactions if so desired. In this project we will
extend the MT method and deliver this methodology to X-ray crystallographers and computational chemists for
use in automated ligand placement within the experimental density during X-ray refinement. This work will
involve development of a new, automated tool to find the active site ligand density and place the ligand within
that density using the MT method. We will commercially deploy the technology, construct graphical user
interfaces for use in MOE, Phenix, and our web-based cloud platform. Finally, this software will be used in real
life structure-based drug discovery problems with our pharmaceutical collaborators (see Letters of Support).
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会议论文
Research and cloud deployment of enhanced sampling methods in MovableType
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批准号:10699159
-
项目类别:
-
资助金额:$20.77万
-
财政年份:2023
-
负责人:Lance M Westerhoff
-
依托单位:
Research and deployment of binding-domain flexible MovableType (MTFlex) for free energy-based affinity prediction and crystallographic structure determination
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批准号:10093097
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项目类别:
-
资助金额:$51.32万
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财政年份:2019
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负责人:Lance M Westerhoff
-
依托单位:
Development and Deployment of the Movable Type Method for Drug Discovery and Desi
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批准号:8781973
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项目类别:
-
资助金额:$16.53万
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财政年份:2014
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负责人:Lance M Westerhoff
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依托单位:
A new approach to solvent determination in QM/MM-based X-ray crystallographic refinement
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批准号:8834159
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项目类别:
-
资助金额:$14.11万
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财政年份:2014
-
负责人:Lance M Westerhoff
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依托单位:
Development and Deployment of the Movable Type Method for Drug Discovery and Desi
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批准号:9032505
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项目类别:
-
资助金额:$56.13万
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财政年份:2014
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负责人:Lance M Westerhoff
-
依托单位:
Development and Deployment of the Movable Type Method for Drug Discovery and Desi
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批准号:8931350
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项目类别:
-
资助金额:$57.06万
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财政年份:2014
-
负责人:Lance M Westerhoff
-
依托单位:
Research and Deployment of a quantum mechanical NMR tool for fragment based drug
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批准号:8721497
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项目类别:
-
资助金额:$13.04万
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财政年份:2013
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负责人:Lance M Westerhoff
-
依托单位:
Research and Deployment of a quantum mechanical NMR tool for fragment based drug
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批准号:8201254
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项目类别:
-
资助金额:$14.79万
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财政年份:2011
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负责人:Lance M Westerhoff
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依托单位:
Research and Deployment of a quantum mechanical NMR tool for fragment based drug
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批准号:8475485
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项目类别:
-
资助金额:$53.21万
-
财政年份:2011
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负责人:Lance M Westerhoff
-
依托单位:
Research and Deployment of a quantum mechanical NMR tool for fragment based drug
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批准号:8449871
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项目类别:
-
资助金额:$53.86万
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财政年份:2011
-
负责人:Lance M Westerhoff
-
依托单位:
Deployment of Quantum Mechanical Pairwise Energy Decomposition for Drug Discovery
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批准号:7929952
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项目类别:
-
资助金额:$9.99万
-
财政年份:2009
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负责人:Lance M Westerhoff
-
依托单位:
Enhancement and Deployment of the Quantum Mechanical X-ray Refinement Model
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批准号:7480712
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项目类别:
-
资助金额:$10.87万
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财政年份:2008
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负责人:Lance M Westerhoff
-
依托单位:
Enhancement and Deployment of the Quantum Mechanical X-ray Refinement Model
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批准号:7708592
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项目类别:
-
资助金额:$63.21万
-
财政年份:2008
-
负责人:Lance M Westerhoff
-
依托单位:
Enhancement and Deployment of the Quantum Mechanical X-ray Refinement Model
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批准号:7742656
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项目类别:
-
资助金额:$62.47万
-
财政年份:2008
-
负责人:Lance M Westerhoff
-
依托单位:
Deployment of Quantum Mechanical Pairwise Energy Decomposition for Drug Discovery
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批准号:7585233
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项目类别:
-
资助金额:$36.0万
-
财政年份:2007
-
负责人:Lance M Westerhoff
-
依托单位:
Deployment of Quantum Mechanical Pairwise Energy Decomposition for Drug Discovery
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批准号:7328262
-
项目类别:
-
资助金额:$9.89万
-
财政年份:2007
-
负责人:Lance M Westerhoff
-
依托单位:
Deployment of Quantum Mechanical Pairwise Energy Decomposition for Drug Discovery
-
批准号:7554710
-
项目类别:
-
资助金额:$40.92万
-
财政年份:2007
-
负责人:Lance M Westerhoff
-
依托单位:
海外基金