title: 2P2I HUNTER: a tool for filtering orthosteric protein-protein interaction modulators via a dedicated support vector machine.
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.
authors.affiliation: 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.
authors.forename: Véronique
authors.initials: V
authors.lastname: Hamon
authors.forename: Raphael
authors.initials: R
authors.lastname: Bourgeas
authors.forename: Pierre
authors.initials: P
authors.lastname: Ducrot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Theret
authors.forename: Laura
authors.initials: L
authors.lastname: Xuereb
authors.forename: Marie Jeanne
authors.initials: MJ
authors.lastname: Basse
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Brunel
authors.forename: Sebastien
authors.initials: S
authors.lastname: Combes
authors.forename: Xavier
authors.initials: X
authors.lastname: Morelli
authors.forename: Philippe
authors.initials: P
authors.lastname: Roche
mesh_terms: D062126:Databases, Chemical; D025941:Protein Interaction Mapping / Q000379:methods*; D054852:Small Molecule Libraries; D060388:Support Vector Machine
chemical_list: D054852:Small Molecule Libraries
keywords: drug design; filtering algorithm; focused chemical library; protein–protein interactions; small molecule inhibitors; support vector machine