3D QSAR & Pharmacophore

How do we predict biological

activity from chemical
structure?

Quantitative Structural Activity Relationship &

Pharmacophore
Limitations of classical QSAR
• Sometimes molecular descriptors alone could not
explain the drug-receptor interactions.

• No representation of stereochemistry or 3D
structure of molecules.

• No graphical output, making interpretation in

familiar chemical terms difficult.

• Higher risk of chance correlations and prediction

failure.
 Dimensions in QSAR
1D-QSAR – Correlating activity with global molecular properties like
pKa, log P.

2D-QSAR – Correlating activity with structural patterns like

connectivity indices, 2D-pharmacophores, without taking into
account the 3D-representation of these properties.

3D-QSAR – Correlating activity with non-covalent interaction fields

surrounding the molecules.

4D-QSAR – Additionally including ensemble of ligand configurations

in 3D-QSAR.

5D-QSAR – Explicitly representing different induced-fit models in

4D-QSAR.

6D-QSAR – Further incorporating different solvation models in 5D-

QSAR.
Steps in 3D QSAR modeling

2D -> 3D
Steps in 3D QSAR modeling
Steps in 3D QSAR modeling
Results of 3D QSAR modeling

Red - Represent increase electronegative substitution increase biological activity.

Blue - Represent increase electropositive substitution increase biological activity
Results of 3D QSAR modeling

Green - Represent increase bulky substitution increase biological activity.

Yellow - Represent decrease bulky substitution increase biological activity
 Pharmacophore modeling
Pharmacophore modeling is an abstract representation
of molecular features necessary for molecular
recognition of a ligand by a biological macromolecule.

The IUPAC defines a pharmacophore to be "an

ensemble of steric and electronic features that is
necessary to ensure the optimal supramolecular
interactions with a specific biological target and to
trigger (or block) its biological response".

A pharmacophore model can show the important

pharmacophore features from a series of structurally
diverse ligands that bind to a common receptor site.
 Pharmacophore features
Pharmacophore features can be:
1) hydrogen bonds acceptors
2) hydrogen bond donors
3) charge interactions
4) hydrophobic areas
5) aromatic rings
6) positive or negative ionizable group
7) the excluded shape or volume is also considered.
Steps in pharmacophore modeling
1. Draw the 2D-structures of all the molecules.
2. Build the 3D-structures and minimize their conformation
energies.
3. Pharmacophore features are identified in the series.
4. Common pharmacophore features of the active
compounds are retained.
5. Pharmacophore features of the inactive are deducted.
6. A model is built relating the pharmacophore fit values
against the biological activity.
7. Results is presented in an interactive graphics of
pharmacophore features.
Pharmacophore result
Pharmacophore result
Why Use Pharmacophore Models ?
• Universal
- Pharmacophore models represent chemical functions,
valid not only for the currently bound, but also
unknown molecules.

• Computationally Efficient
- Due to their simplicity, they are suitable for large scale
virtual screening (>109 compounds, also in parallel
settings).

• Comprehensive & Editable

- Selectivity-tuning by adding or omitting chemical
feature constraints, information can be easily traced
back.