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

Chemical Science
D RekerG Schneider

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.

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Citations

Dec 16, 2017·Nature Reviews. Drug Discovery·Gisbert Schneider
Feb 2, 2018·Molecular Informatics·Dino OglicThomas Gärtner
Dec 6, 2019·Nature Reviews. Drug Discovery·Petra SchneiderGisbert Schneider
Aug 17, 2019·Chembiochem : a European Journal of Chemical Biology·Dominique BrunsGisbert Schneider
Sep 26, 2019·Angewandte Chemie·Connor W ColeyKlavs F Jensen
May 30, 2020·Journal of Computer-aided Molecular Design·Nathan BrownNadine Schneider
Mar 7, 2017·Future Medicinal Chemistry·Daniel RekerJ B Brown
Dec 15, 2017·Journal of Cheminformatics·Samuel BoobierJohn B O Mitchell
Sep 22, 2016·Molecular Informatics·Francesca GrisoniGisbert Schneider
Jul 28, 2018·Science Advances·Mariya PopovaAlexander Tropsha
Apr 17, 2019·Nature Chemistry·Daniel RekerTiago Rodrigues
Sep 9, 2016·Angewandte Chemie·Gisbert SchneiderKarl-Heinz Altmann
Mar 19, 2020·Cell Reports·Daniel RekerGiovanni Traverso
Mar 27, 2021·Nature Nanotechnology·Daniel RekerGiovanni Traverso
Dec 1, 2019·Drug Discovery Today. Technologies·Daniel Reker
Jul 9, 2021·The Journal of Organic Chemistry·A Filipa AlmeidaTiago Rodrigues
Jul 12, 2019·Chemical Reviews·Xin YangShengyong Yang
Feb 7, 2019·Journal of Chemical Information and Modeling·Ruben BuendiaErnst Ahlberg

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Software Mentioned

KNIME
PAINS
CATS2
PyMOL
GOLD
DiscoverX
MOE
PFROSST
ChEMBL19
SciFinder

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