Computational Chemistry

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• Computational Chemistry

Structure-based Drug Design
Chemoinformatics
Molecular Graphics
Molecular Modelling
Rational Drug Design
3D-QSAR
Computer-assisted Drug Discovery (CADD)
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• The aim of Molecular Modelling in the
  pharmaceutical industry
• To support medicinal chemists to make "better"
  compounds in order to speed up the drug discovery
  process

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• Issues in Molecular Modelling
• Interactive computer graphics
• Small molecule modelling
• Protein modelling
• Protein-Ligand interactions
• Ligand design

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• Issues in Molecular Modelling (I)
• Interactive computer graphics
• Display and manipulation of 3D structures

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• Issues in Molecular Modelling (II)
• Small molecule modelling
• Structure generation
• Molecular mechanics/dynamics (MM/MD)
• Quantum mechanics (QM)
• Conformational analysis
• Calculation of physicochemical properties
• Comparison of molecules

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• Issues in Molecular Modelling (III)
• Protein modelling
• Sequence comparison
• Homology modelling
• Simulation of protein folding
• Protein dynamics

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• Issues in Molecular Modelling (IV)
• Protein-Ligand interactions
• Docking of ligands
• Calculation of binding affinities
• Ligand design
• Search in 3D databases
• Structure-based (de novo) ligand design

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• Issues in Molecular Modelling (I)
• Interactive Computergraphics
• Display and manipulation of 3D structures

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• One word of caution...

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• Prediction of binding constants
• The Holy Grail of Computational Chemistry!

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• Dose-response measurement
• Ligand with moderate affinity

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• Dose-response measurement
• Ligand with high affinity

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• Binding constant is a function of free energy!

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Correlation between -logKi and ?G at body
temperature (310K)
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In order to predict binding constants ...
...all we have to do is to calculate ?G of the
protein-ligand complex formation!
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Entropy change - transition from ordered to
disordered

• Entropically favourable contributions
• Displacement of water from protein pockets
• Displacement of water due to desolvation of the
  ligand
• Caution For polar surface patches, balance
  between changes in entropy and enthalpy is hard
  to predict!!!
• Entropically unfavourable contributions
• "freezing" of rotatable bonds (in ligand and
  protein)
• loss of translational and rotational degrees of
  freedom

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Entropy and Enthalpy change upon ligand binding