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Mapping ligand interactions of bromodomains BRD4 and ATAD2 with FragLites and PepLites - halogenated probes of druglike and peptide-like molecular interactions

DOI: 10.1021/acs.jmedchem.2c01357 DOI Help

Authors: Gemma Davison (Newcastle University) , Mathew P. Martin (Newcastle University) , Shannon Turberville (Newcastle University) , Selma Dormen (Newcastle University) , Richard Heath (Newcastle University) , Amy B. Heptinstall (Newcastle University) , Marie Lawson (Newcastle University) , Duncan C. Miller (Newcastle University) , Yi Min Ng (Newcastle University) , James N. Sanderson (Newcastle University) , Ian Hope (Newcastle University) , Daniel Wood (Newcastle University) , CĂ©line Cano (Newcastle University) , Jane A. Endicott (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Ian R. Hardcastle (Newcastle University) , Martin E. M. Noble (Newcastle University) , Michael J. Waring (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: November 2022

Open Access Open Access

Abstract: The development of ligands for biological targets is critically dependent on the identification of sites on proteins that bind molecules with high affinity. A set of compounds, called FragLites, can identify such sites, along with the interactions required to gain affinity, by X-ray crystallography. We demonstrate the utility of FragLites in mapping the binding sites of bromodomain proteins BRD4 and ATAD2 and demonstrate that FragLite mapping is comparable to a full fragment screen in identifying ligand binding sites and key interactions. We extend the FragLite set with analogous compounds derived from amino acids (termed PepLites) that mimic the interactions of peptides. The output of the FragLite maps is shown to enable the development of ligands with leadlike potency. This work establishes the use of FragLite and PepLite screening at an early stage in ligand discovery allowing the rapid assessment of tractability of protein targets and informing downstream hit-finding.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 14/11/2022 08:23


Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening