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2 October 2013
Outline
I. Traditional vs. Computational Drug Design
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Very expensive ($300M) Extremely low yield: over the last 50 years, 500,000 compounds have been tested for anti-cancer, only 25 are in wide use today
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United States: 45% market share in 2006 Growth rate: USA 22%, Europe 25%
source: Business Insights, 2008
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Pharmaceutical corporations using CADD: Pfizer, GlaxoSmithKline, Novartis (using FOCUS), Sanofi, AstraZeneca, Abbott
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Scientific Background
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Docking
Predicting the best orientation and conformation of a small molecule (drug) when bound to a target larger receptor molecule in order to form a stable complex Accordingly predicting the energy, binding affinity, and stability of the complex molecule Simulate the molecular recognition process Activation of the target protein for desired functionality
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Ligand structure
Protein tertiary structure 2 October 2013 15
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1. Representation of the molecules 2. Searching the orientation/conformation space for optimal poses 3. Evaluation of the potential solutions
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I. Representation
Geometric description
Energy terms Pharmacophore fingerprints
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Geometric Description
Coordinates of atoms in 3-dimensional space
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Energy Terms
Van der Waals force: physical (rather than chemical bonding)
Coulomb force: electrostatic force , = , 4 , Solvation energy Etc.
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Pharmacophore Fingerprints
It is basically chemical features of the underlying complex
Chemical interactions classified into six types: hydrogen bond with ligand acceptor, hydrogen bond with ligand donor, etc
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problem
(matching
two
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3. Scoring Function
Evaluating potential solutions
A measure of the fit of a ligand into the active site of receptor protein
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Scoring Function
1. Scoring power
2. Ranking power
3. Docking power
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Scoring Power
Predicting Protein-Ligand binding affinity An empirical value (measured in lab,)
Ranking Power
The ability to correctly rank a given set of ligands with known binding modes when bound to the same protein according to their true binding affinities.
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Docking Power
The ability to identify the correct binding mode of a ligand from a set of computationally generated poses
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Docking Algorithm
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Conclusion
CADD strongly being promoted Economical benefits (in Egypt): Bioinformatics + Pharmaceuticals Very multi-disciplinary
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THANK YOU
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