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Prediction of Ligand Binding Site

Prediction of Ligand Binding Site on the Target Protein

This Q-MOL computational job allows for reliable prediction of the ligand binding site.  The molecular structure of a confirmed hit can be used as a probe to systematically scan the molecular surface of the protein to reliably predict its bind binding site.

Consider the following example: prediction of binding site of certain β-catenin modulators.  The target protein structure is β-catenin armadillo repeat domain.

 

Β-catenin armadillo repeat domain is displayed as blue molecular surface, Lef/Tcf4 and Bcl9 peptides are green helices.  The molecular surface of the target protein was scanned by ligands shown next to protein structure (e.g. PRI724).

The probabilities of a ligand binding to a particular spot on the surface of a protein are depicted by colored spheres: blue/small – low probability; red/big – high probability.

The Pymol session result file of the job will contain the target structure and generated probabilities sphere objects.

 

Predicting Ligand Specificity from Molecular Surface Scans

The molecular surface scanning allows accessing how specific a given ligand is toward the selected protein target.  The more specific the ligand – the tighter the predicted binding spot, ideally it should be just single binding spot.

A simple visual inspection of the surface scans reveals the ligand specificity trend: PRI724 is the most specific, BC2059 is the least specific.  These predictions correlate well with ligands biological activity: PRI724 is in clinical trials, while BC2059 is the least active from the list of ligands.

The surface scanning data can be processed into a single numeric value  describing relative ligand specificity: a specificity index.

The specificity index is an invaluable tool when rationalizing medicinal chemistry efforts.  The proposed ligand structures can be evaluated for specificity by surface scanning.  This methodology is significantly more thorough than a conventional protein ligand docking.

The SpecificityIndex.dat file of the results archive will contain the specificity index data for each ligand.