Chemical Screening by Time-Resolved X-Ray Scattering To Discover Allosteric Probes

Authors

Chris A Brosey
Todd M Link
Runze Shen
Davide Moiani
Kathryn Burnett
Greg L Hura
Darin E Jones
John A Tainer

Publication Date

9-1-2024

Journal

Nature Chemical Biology

Abstract

Drug discovery relies on efficient identification of small-molecule leads and their interactions with macromolecular targets. However, understanding how chemotypes impact mechanistically important conformational states often remains secondary among high-throughput discovery methods. Here, we present a conformational discovery pipeline integrating time-resolved, high-throughput small-angle X-ray scattering (TR-HT-SAXS) and classic fragment screening applied to allosteric states of the mitochondrial import oxidoreductase apoptosis-inducing factor (AIF). By monitoring oxidized and X-ray-reduced AIF states, TR-HT-SAXS leverages structure and kinetics to generate a multidimensional screening dataset that identifies fragment chemotypes allosterically stimulating AIF dimerization. Fragment-induced dimerization rates, quantified with time-resolved SAXS similarity analysis (k

Keywords

Allosteric Regulation, Structure-Activity Relationship, Apoptosis Inducing Factor, Scattering, Small Angle, X-Ray Diffraction, Humans, Drug Discovery, Models, Molecular, Kinetics, Small Molecule Libraries

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Associated Data

PMID: 38671223