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Small-molecule inhibitor starting points learned from protein-protein interaction inhibitor structure.

ABSTRACT: Protein-protein interactions (PPIs) are a promising, but challenging target for pharmaceutical intervention. One approach for addressing these difficult targets is the rational design of small-molecule inhibitors that mimic the chemical and physical properties of small clusters of key residues at the protein-protein interface. The identification of appropriate clusters of interface residues provides starting points for inhibitor design and supports an overall assessment of the susceptibility of PPIs to small-molecule inhibition.We extract Small-Molecule Inhibitor Starting Points (SMISPs) from protein-ligand and protein-protein complexes in the Protein Data Bank (PDB). These SMISPs are used to train two distinct classifiers, a support vector machine and an easy to interpret exhaustive rule classifier. Both classifiers achieve better than 70% leave-one-complex-out cross-validation accuracy and correctly predict SMISPs of known PPI inhibitors not in the training set. A PDB-wide analysis suggests that nearly half of all PPIs may be susceptible to small-molecule inhibition.

SUBMITTER: Koes DR

PROVIDER: S-EPMC3307105 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Small-molecule inhibitor starting points learned from protein-protein interaction inhibitor structure.

Koes David Ryan DR Camacho Carlos J CJ

Bioinformatics (Oxford, England) 20111230 6

<h4>Motivation</h4>Protein-protein interactions (PPIs) are a promising, but challenging target for pharmaceutical intervention. One approach for addressing these difficult targets is the rational design of small-molecule inhibitors that mimic the chemical and physical properties of small clusters of key residues at the protein-protein interface. The identification of appropriate clusters of interface residues provides starting points for inhibitor design and supports an overall assessment of the ...[more]

PMID: 22210869

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Dataset Information

Small-molecule inhibitor starting points learned from protein-protein interaction inhibitor structure.

Publications

Small-molecule inhibitor starting points learned from protein-protein interaction inhibitor structure.

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