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A simple and fuzzy method to align and compare druggable ligand-binding sites
Claire Schalon1, Jean-Sébastien Surgand, Esther Kellenberger
1Bioinformatics of the Drug, Institut Gilbert Laustriat, CNRS UMR 7175-LC1, 74 route du Rhin, F-67400 Illkirch.
Proteins
|January 5, 2008
Summary
A new computational method, SiteAlign, quantifies distances between protein binding sites using a cavity fingerprint. This approach aids in drug discovery by identifying similar sites and predicting ligand targets effectively.
Area of Science:
- Computational chemistry
- Structural biology
- Drug discovery
Background:
- Accurate measurement of distances between protein cavities is crucial for understanding protein function and designing targeted drugs.
- Existing methods may struggle with variations in cavity size and local residue conformations.
Purpose of the Study:
- To introduce a novel computational method for measuring distances between druggable protein cavities.
- To develop a robust tool for protein active site comparison and ligand-target prediction.
Main Methods:
- A new program, SiteAlign, was developed to create a 'cavity fingerprint' by projecting eight topological and physicochemical properties onto a discretised sphere at the binding site center.
- This method normalizes distances between sites of varying sizes and allows for structural alignment through sphere manipulation.
- It incorporates global amino acid properties, offering robustness against local residue variations.
Main Results:
- The SiteAlign method was successfully applied to measure distances between 376 active site pairs.
- It demonstrated effectiveness in computing cross-similarity within protein families.
- The method accurately predicted targets for promiscuous ligands through virtual screening.
Conclusions:
- SiteAlign provides a robust and versatile approach for detecting local similarity between protein active sites, even those of different sizes.
- The method can effectively discriminate between protein subfamilies and is valuable for virtual screening and drug discovery efforts.
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