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 D ragon 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.