title: Designing focused chemical libraries enriched in protein-protein interaction inhibitors using machine-learning methods.
abstract: Protein-protein interactions (PPIs) may represent one of the next major classes of therapeutic targets. So far, only a minute fraction of the estimated 650,000 PPIs that comprise the human interactome are known with a tiny number of complexes being drugged. Such intricate biological systems cannot be cost-efficiently tackled using conventional high-throughput screening methods. Rather, time has come for designing new strategies that will maximize the chance for hit identification through a rationalization of the PPI inhibitor chemical space and the design of PPI-focused compound libraries (global or target-specific). Here, we train machine-learning-based models, mainly decision trees, using a dataset of known PPI inhibitors and of regular drugs in order to determine a global physico-chemical profile for putative PPI inhibitors. This statistical analysis unravels two important molecular descriptors for PPI inhibitors characterizing specific molecular shapes and the presence of a privileged number of aromatic bonds. The best model has been transposed into a computer program, PPI-HitProfiler, that can output from any drug-like compound collection a focused chemical library enriched in putative PPI inhibitors. Our PPI inhibitor profiler is challenged on the experimental screening results of 11 different PPIs among which the p53/MDM2 interaction screened within our own CDithem platform, that in addition to the validation of our concept led to the identification of 4 novel p53/MDM2 inhibitors. Collectively, our tool shows a robust behavior on the 11 experimental datasets by correctly profiling 70% of the experimentally identified hits while removing 52% of the inactive compounds from the initial compound collections. We strongly believe that this new tool can be used as a global PPI inhibitor profiler prior to screening assays to reduce the size of the compound collections to be experimentally screened while keeping most of the true PPI inhibitors. PPI-HitProfiler is freely available on request from our CDithem platform website, www.CDithem.com.
authors.affiliation: Inserm UMR-S 973/MTi, University Paris Diderot, Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Reynès
authors.forename: Hélène
authors.initials: H
authors.lastname: Host
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Camproux
authors.forename: Guillaume
authors.initials: G
authors.lastname: Laconde
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.forename: Anne
authors.initials: A
authors.lastname: Mazars
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
authors.forename: Robin
authors.initials: R
authors.lastname: Fahraeus
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.forename: Olivier
authors.initials: O
authors.lastname: Sperandio
mesh_terms: D001185:Artificial Intelligence; D006801:Humans; D016247:Information Storage and Retrieval / Q000379:methods*; D010363:Pattern Recognition, Automated / Q000379:methods*; D025941:Protein Interaction Mapping / Q000379:methods*; D020543:Proteome / Q000737:chemistry* / Q000378:metabolism*; D054852:Small Molecule Libraries; D012984:Software
chemical_list: D020543:Proteome; D054852:Small Molecule Libraries