Chiral Cliffs: Investigating the Influence of Chirality on Binding Affinity

ChemMedChem
Nadine SchneiderPeter Ertl

Abstract

Chirality is understood by many as a binary concept: a molecule is either chiral or it is not. In terms of the action of a structure on polarized light, this is indeed true. When examined through the prism of molecular recognition, the answer becomes more nuanced. In this work, we investigated chiral behavior on protein-ligand binding: when does chirality make a difference in binding activity? Chirality is a property of the 3D structure, so recognition also requires an appreciation of the conformation. In many situations, the bioactive conformation is undefined. We set out to address this by defining and using several novel 2D descriptors to capture general characteristic features of the chiral center. Using machine-learning methods, we built different predictive models to estimate if a chiral pair (a set of two enantiomers) might exhibit a chiral cliff in a binding assay. A set of about 3800 chiral pairs extracted from the ChEMBL23 database was used to train and test our models. By achieving an accuracy of up to 75 %, our models provide good performance in discriminating chiral cliffs from non-cliffs. More importantly, we were able to derive some simple guidelines for when one can reasonably use a racemate and when an enantiop...Continue Reading

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Citations

Jul 9, 2020·Future Medicinal Chemistry·Huabin Hu, Jürgen Bajorath
Jun 11, 2020·Future Science OA·Huabin Hu, Jürgen Bajorath
May 6, 2020·Journal of Computer-aided Molecular Design·Dagmar StumpfeJürgen Bajorath
Mar 25, 2019·Journal of Cheminformatics·Célien JacquemardEsther Kellenberger
Jan 23, 2021·RSC Medicinal Chemistry·Huabin Hu, Jürgen Bajorath
Jun 3, 2021·International Journal of Molecular Sciences·Andrzej Bak
Aug 4, 2021·Molecular Informatics·Aleksandra NikonenkoPavel Polishchuk
Dec 12, 2018·Journal of Medicinal Chemistry·Maxim B NawrozkijDante Rotili
Sep 19, 2019·ACS Omega·Dagmar StumpfeJürgen Bajorath

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