Spinning up new predictors: NMR and aqueous solubility · PDF fileSpinning up new predictors:...
Transcript of Spinning up new predictors: NMR and aqueous solubility · PDF fileSpinning up new predictors:...
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Solutions for Cheminformatics
Spinning up new predictors: NMR and aqueous solubility
Csaba Fábri
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Agenda
Nuclear magnetic resonance (NMR) spectroscopy
• Introduction of NMR spectroscopy
• Prediction of spectrum parameters
• Validation of the chemical shift prediction model
• NMR Predictor demonstration
• NMR future plans
Solubility (development has been started)
• Brief summary of the solubility model
• Solubility Predictor demonstration
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NMR introduction: ethanol 1H NMR
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Chemaxon's novel NMR Predictor overview
Fast and accurate 1H and 13C NMR prediction for
standard organic molecules
Easy-to-use graphical user interface
Comparison of experimental and predicted spectra
Ready for web (MarvinSketch applet)
Another useful predictor in Chemaxon's Discovery
Toolkit
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Chemical shift prediction overview
Aim: fast and accurate prediction of chemical shifts
First approach: HOSE code technology
Second approach: QSPR
Mixed model: combination of HOSE and QSPR
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HOSE code-based chemical shift prediction
C-3;*C*CO(*CC,*C,C/*C,=OO,*&,=OC/)
query: ? ppm 1. hit: 150.4 ppm
2. hit: 150.8 ppm
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Decision tree-based chemical shift prediction
Physicochemical and topological descriptors
Model fitting: Decision tree with multilinear least-
squares regression (MLR)
NMRShiftDB (http://nmrshiftdb.nmr.uni-koeln.de)
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Chemical shift descriptor set
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J. Chem. Inf. Comput. Sci. 40, 1169 (2000)
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Mixed chemical shift model
HOSE search is started with an initial radius of 6,
radius is consecutively decreased until a threshold is reached
Are there any hits with a radius greater equal than a threshold?
(threshold: 3 for 13C NMR, 4 for 1H NMR)
Hits with the largest radius are
averaged Decision tree-based model is
invoked
yes no
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Chemical shift model validation: 5.10 vs 5.11.1
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13C NMR 5.10 5.11.1
< 5 ppm 77 % 88 %
< 10 ppm 93 % 97 %
1H NMR 5.10 5.11.1
< 0.5 ppm 81 % 91 %
< 1.0 ppm 93 % 98 %
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Coupling constant prediction
HH coupling (3J)
CF coupling (1J and 2J, new in 5.11)
HF coupling (2J, 3J and 4J, new in 5.11)
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Diastereotopic protons are distinguished
1212
2.49 ppm
2.52 ppm
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Example: mixed chemical shift model
1H NMR chemical shifts (ppm)
Atom Pred. Exp. HOSE radius HOSE hits
18,19, 20 2.20 2.24 5 4
16,17 3.89 4.09 - -
14 7.17 7.16 6 2
13,15 7.33 7.32 5 2
Decision tree-based shift model is used if there are no HOSE hits!
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Case study: 2,4-pentanedione 13C NMR
measured
predicted
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Tautomerization effect
T2: 28 %
T1: 72 %measured
predicted
2T1
2T1
T1
T2
T2T
2
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NMR future plans
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Extend the NMR chemical shift training set
Support more NMR data formats for import/export
NMR prediction on www.chemicalize.org
Give the user the possibility to train the NMR chemical
shift model
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Solubility Predictor
Brief summary:
• QSPR model
• Physicochemical and topological descriptors
• Training for experimental intrinsic solubilities
List of relevant features:
• Prediction of intrinsic solubilities
• Prediction of pH-dependent solubility curves
Demonstration
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Summary
Fast and accurate 1H and 13C NMR spectrum prediction for standard organic molecules
Development of the Solubility Predictor has been started
Any feedback is appreciated:
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Acknowledgements
Calculations team members:Zsolt Mohácsi, Imre Barna, Rita Veréb, István Rábel, József Szegezdi, Viktória Pálfi
NMR consultant:Csaba Peltz
NMR icons:János Papdeák
Application scientists: Iván Solt, Attila Szabó, Krisztián Niesz
NMRShiftDB:Stefan Kuhn
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