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J R Soc Interface. 2013 Nov 6;11(90):20130860. doi: 10.1098/rsif.2013.0860. Print 2014 Jan 6.

2P2I HUNTER: a tool for filtering orthosteric protein-protein interaction modulators via a dedicated support vector machine.

Author information

1
Laboratory of integrative Structural and Chemical Biology (iSCB), Centre de Recherche en Cancérologie de Marseille (CRCM); CNRS UMR 7258, INSERM U 1068, Institut Paoli-Calmettes; and Aix-Marseille Universités, , Marseille 13009, France.

Abstract

Over the last 10 years, protein-protein interactions (PPIs) have shown increasing potential as new therapeutic targets. As a consequence, PPIs are today the most screened target class in high-throughput screening (HTS). The development of broad chemical libraries dedicated to these particular targets is essential; however, the chemical space associated with this 'high-hanging fruit' is still under debate. Here, we analyse the properties of 40 non-redundant small molecules present in the 2P2I database (http://2p2idb.cnrs-mrs.fr/) to define a general profile of orthosteric inhibitors and propose an original protocol to filter general screening libraries using a support vector machine (SVM) with 11 standard Dragon molecular descriptors. The filtering protocol has been validated using external datasets from PubChem BioAssay and results from in-house screening campaigns. This external blind validation demonstrated the ability of the SVM model to reduce the size of the filtered chemical library by eliminating up to 96% of the compounds as well as enhancing the proportion of active compounds by up to a factor of 8. We believe that the resulting chemical space identified in this paper will provide the scientific community with a concrete support to search for PPI inhibitors during HTS campaigns.

KEYWORDS:

drug design; filtering algorithm; focused chemical library; protein–protein interactions; small molecule inhibitors; support vector machine

PMID:
24196694
PMCID:
PMC3836326
DOI:
10.1098/rsif.2013.0860
[Indexed for MEDLINE]
Free PMC Article

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