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Multi-objective active machine learning rapidly improves structure-activity models and reveals new protein-protein interaction inhibitors.

ABSTRACT: Active machine learning puts artificial intelligence in charge of a sequential, feedback-driven discovery process. We present the application of a multi-objective active learning scheme for identifying small molecules that inhibit the protein-protein interaction between the anti-cancer target CXC chemokine receptor 4 (CXCR4) and its endogenous ligand CXCL-12 (SDF-1). Experimental design by active learning was used to retrieve informative active compounds that continuously improved the adaptive structure-activity model. The balanced character of the compound selection function rapidly delivered new molecular structures with the desired inhibitory activity and at the same time allowed us to focus on informative compounds for model adjustment. The results of our study validate active learning for prospective ligand finding by adaptive, focused screening of large compound repositories and virtual compound libraries.

SUBMITTER: Reker D

PROVIDER: S-EPMC6013791 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Multi-objective active machine learning rapidly improves structure-activity models and reveals new protein-protein interaction inhibitors.

Reker D D Schneider P P Schneider G G

Chemical science 20160310 6

Active machine learning puts artificial intelligence in charge of a sequential, feedback-driven discovery process. We present the application of a multi-objective active learning scheme for identifying small molecules that inhibit the protein-protein interaction between the anti-cancer target CXC chemokine receptor 4 (CXCR4) and its endogenous ligand CXCL-12 (SDF-1). Experimental design by active learning was used to retrieve informative active compounds that continuously improved the adaptive s ...[more]

PMID: 30155037

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Project description: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.

Dataset Information

Multi-objective active machine learning rapidly improves structure-activity models and reveals new protein-protein interaction inhibitors.

Publications

Multi-objective active machine learning rapidly improves structure-activity models and reveals new protein-protein interaction inhibitors.

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