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Hamon V, Bourgeas R, Ducrot P, et al. 2P2I HUNTER: a tool for filtering orthosteric protein-protein interaction modulators via a dedicated support vector machine. J R Soc Interface. 2013;11(90):20130860doi: 10.1098/rsif.2013.0860.
Hamon, V., Bourgeas, R., Ducrot, P., Theret, I., Xuereb, L., Basse, M. J., Brunel, J. M., Combes, S., Morelli, X., & Roche, P. (2014). 2P2I HUNTER: a tool for filtering orthosteric protein-protein interaction modulators via a dedicated support vector machine. Journal of the Royal Society, Interface, 11(90), 20130860. https://doi.org/10.1098/rsif.2013.0860
Hamon, Véronique, et al. "2P2I HUNTER: a tool for filtering orthosteric protein-protein interaction modulators via a dedicated support vector machine." Journal of the Royal Society, Interface vol. 11,90 (2014): 20130860. doi: https://doi.org/10.1098/rsif.2013.0860
Hamon V, Bourgeas R, Ducrot P, Theret I, Xuereb L, Basse MJ, Brunel JM, Combes S, Morelli X, Roche P. 2P2I HUNTER: a tool for filtering orthosteric protein-protein interaction modulators via a dedicated support vector machine. J R Soc Interface. 2013 Nov 06;11(90):20130860. doi: 10.1098/rsif.2013.0860. Print 2014 Jan 06. PMID: 24196694; PMCID: PMC3836326.
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J R Soc Interface. 2013 Nov 06;11(90):20130860. doi: 10.1098/rsif.2013.0860. Print 2014 Jan 06.

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

Journal of the Royal Society, Interface

Véronique Hamon, Raphael Bourgeas, Pierre Ducrot, Isabelle Theret, Laura Xuereb, Marie Jeanne Basse, Jean Michel Brunel, Sebastien Combes, Xavier Morelli, Philippe Roche

Affiliations

  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.

PMID: 24196694 PMCID: PMC3836326 DOI: 10.1098/rsif.2013.0860

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

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