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• X-ray crystallography• Cambridge Structural Database• Protein Data Bank• Comparing biological activity of

non-rigid 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 compoundsx,y,z correspond to lengths of three sides of trianglesGraphing allows identification of distinct pharmacophoresOmit 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• 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 sitewhen 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

Inhibitors similar to substrateor cofactor

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