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Molecular mechanics
• Classical physics, treats atoms as spheres
• Calculations are rapid, even for large
molecules
• Useful for studying conformations
• Cannot calculate electronic properties
Energy minimization
Visualizing molecules
Quantum Mechanics
• Considers interactions between
electrons and neutrons
• Can calculate electronic properties
• Slower calculations than molecular
mechanics
• Ab initio vs. semi-empirical
Partial charges on histamine
Partial charges on protonated
histamine
Effect of delocalized charge
Molecular electrostatic potentials
(MEPs)
Conformational analysis
Molecular Dynamics
Structure Comparison (2D)
Structure Comparison (3D)
Identifying the active conformation
of ligand
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X-ray crystallography
Cambridge Structural Database
Protein Data Bank
Comparing biological activity of nonrigid ligands with various rigid ligands
3D Pharmacophore Identification
• X-ray crystal structure of protein-ligand
complex (from PDB)
• Comparison of active compounds (when
target structure is unknown)
• Automated identification of
pharmacophores
Automated identification of
pharmacophores
• Generate range of conformers
• For each conformer, define set of pharmacophore
triangles
• Another structure is analyzed
• Pharmacophore triangles compared to those for
previous structures
Pharmacophore plot
Use pharmacophore triangles common to all active
compounds
x,y,z correspond to lengths of three sides of triangles
Graphing allows identification of distinct pharmacophores
Omit triangles involving non-essential binding groups
Docking procedures
• X-ray crystal structure of target protein
with binding region highlighted
• Place ligand within active site with
different orientations to identify best
orientation
• Simplest approach—treat ligand and
target as non-flexible
DOCK
ChemX: Analyzing potential binding centers
Compare ligand pharmacophores to those in binding site
Bump filter
Reject conformations
which involve bad
steric interactions
Constructing protein model
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Need primary amino acid sequence
Compare to other proteins
Need X-ray structure of related protein
Arrange new protein to match
sequences similar to known protein
• Determine structure of connecting
sequences by comparison to proteins in
databases or with loops
Model protein
• Side chains added in energetically
favorable conformations
• Energy minimization
• Structure refined with molecular
dynamics
• Use this model protein to analyze
potential ligands
Constructing binding site
when protein structure is unknown
• Range of structurally diverse
compounds with varying activities
• Align molecules to match up
pharmacophores
• Potential energy grid with probes to
measure interaction energies
Potential energy probe to find binding site
De novo design
• In theory, design drug for target given
structure of binding site
• In reality, design good lead compound
• Used to get drugs unlike natural
substrates to minimize side effects
Thymidylate synthase
Thymidylate synthase
cofactor
Inhibitors similar to substrate
or cofactor
CB3717 binding to thymidylate
synthase active site
• Create empty binding
site from X-ray crystal
structure of protein plus
inhibitor
• Found hydrophobic
area near where
pteridine group is bound
De novo design of Thymidylate
synthase inhibitor
Intended vs. actual interactions
Revised structure
Binding interactions of new structure
Modified inhibitor