Strong nonadditivity as a key structure-activity relationship feature: distinguishing structural changes from assay artifacts

Journal of Chemical Information and Modeling
Christian KramerKlaus R Liedl

Abstract

Nonadditivity in protein-ligand affinity data represents highly instructive structure-activity relationship (SAR) features that indicate structural changes and have the potential to guide rational drug design. At the same time, nonadditivity is a challenge for both basic SAR analysis as well as many ligand-based data analysis techniques such as Free-Wilson Analysis and Matched Molecular Pair analysis, since linear substituent contribution models inherently assume additivity and thus do not work in such cases. While structural causes for nonadditivity have been analyzed anecdotally, no systematic approaches to interpret and use nonadditivity prospectively have been developed yet. In this contribution, we lay the statistical framework for systematic analysis of nonadditivity in a SAR series. First, we develop a general metric to quantify nonadditivity. Then, we demonstrate the non-negligible impact of experimental uncertainty that creates apparent nonadditivity, and we introduce techniques to handle experimental uncertainty. Finally, we analyze public SAR data sets for strong nonadditivity and use recourse to the original publications and available X-ray structures to find structural explanations for the nonadditivity observed. W...Continue Reading

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Citations

Oct 27, 2015·Journal of Chemical Information and Modeling·Julian E FuchsKlaus R Liedl
Mar 15, 2016·Journal of Chemical Information and Modeling·Christoph GrebnerChristian Tyrchan
Jan 13, 2017·Journal of Chemical Information and Modeling·Michael SchauperlKlaus R Liedl
Dec 16, 2017·Nature Reviews. Drug Discovery·Gisbert Schneider
Mar 13, 2020·PLoS Neglected Tropical Diseases·Lorenzo CianniCarlos A Montanari
Jun 9, 2016·Journal of Computer-aided Molecular Design·Johannes R LoefflerKlaus R Liedl
Feb 2, 2019·Journal of Cheminformatics·Peter W Kenny
Feb 2, 2021·Journal of Chemical Information and Modeling·Mahendra AwaleChristian Kramer
Nov 19, 2019·European Journal of Medicinal Chemistry·Sabria ElderwishLaurent Désaubry
Sep 12, 2019·Journal of Chemical Information and Modeling·Christian Kramer
Nov 28, 2020·Journal of Chemical Information and Modeling·Hans MatterGerhard Hessler
Nov 14, 2017·Journal of Chemical Information and Modeling·Samo TurkSimone Fulle
Oct 23, 2018·ACS Medicinal Chemistry Letters·Laurent Gomez
Sep 4, 2020·Biophysical Journal·Stephen BoultonGiuseppe Melacini
Nov 12, 2021·Journal of Chemical Information and Modeling·Grigorii V AndrianovJohn Karanicolas

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Methods Mentioned

BETA
X-ray

Software Mentioned

RDKit
ChEMBL
Free Wilson
CHEMBL18
maestro

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