Table of Contents
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Outline
ADME/Tox Property Prediction: Challenges in Medicinal Chemistry
Traditional Drug Discovery Scheme
In silico prediction of ADME properties
QSPR/ADME Modeling Procedure
Chemistry In/Out Modeling
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TAE Descriptors
TAE descriptors continued ...
Electron Density-Derived Descriptors
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WCD Descriptors: Discrete Wavelet Transformation
Discrete Wavelet Transformation: Pyramid Algorithm
Wavelet Representations of High-Resolution Molecular Surface Property Densities. (1,2,10 and 20 Coefficient Decompositions)
Electron Density-Derived Property Modeling: Wavelet Coefficient Descriptors (WCDs)
Electron Density-Derived Molecular Properties: Wavelet Coefficient Descriptors (WCDs)
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PEST descriptors continued ...
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Data Analysis Techniques
Approaches to feature selection
Practical Issues
Validation Methodology
Validation Methodology continued...
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ADME Problem: Human Intestinal Absorption
Approximate ADME Prediction
Optimization of bioavailability by using the “rule of five”
Bioassay: Caco-2 Permeability
Intestinal Absorption Mechanisms
Human Intestinal Absorption Barriers
The Caco-2 cell line
Caco-2 Assays
Public Caco-2 Data Sources
LSER and TLSER methods
Molecular Polar Surface Area (PSA and PSAd)
Monte Carlo Simulation methods
Quantum Mechanics-Based Descriptors
Atom-based descriptors
Other methods involved in ADME prediction
Rapid Electron Density-Derived Descriptor Methods – DDASSL
Bagged Non-linear SVM (RBF) Models Caco-2 : 718 TAE/PEST Descriptors
Bagged Non-linear SVM (RBF) Models Caco-2 : 31 Variables
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Star Plot of ABSDRN6
Bagged Non-linear SVM (RBF) Models Caco-2 : 15 Variables
Visualization of 15 Selected Descriptors
Analysis: Starplot of a.don
Analysis: Starplot of SlogP.VSA0
Chemical Insights
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Future Directions
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Acknowledgements
That’s all folks…
Wavelet Representations of High-Resolution Molecular Surface Property Densities.
Flowchart of SVMs
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Hybrid TAE/SHAPE
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Summary
Future Development
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Wrapper Feature Selection Results
Iterative Bagged Feature Selection Results
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Atom-based descriptors
LSER and TLSER methods
Molecular Polar Surface Area (PSA and PSAd)
Monte Carlo Simulation methods
Quantum Mechanics-Based Descriptors
Other methods involved in ADME prediction
Recent Results
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