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Fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries

DOI: 10.1021/acs.jmedchem.2c01004 DOI Help

Authors: Anna Carbery (Diamond Light Source; University of Oxford) , Rachael Skyner (Diamond Light Source) , Frank Von Delft (Diamond Light Source; University of Oxford) , Charlotte M. Deane (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 291

State: Published (Approved)
Published: August 2022

Open Access Open Access

Abstract: Current fragment-based drug design relies on the efficient exploration of chemical space by using structurally diverse libraries of small fragments. However, structurally dissimilar compounds can exploit the same interactions and thus be functionally similar. Using three-dimensional structures of many fragments bound to multiple targets, we examined if a better strategy for selecting fragments for screening libraries exists. We show that structurally diverse fragments can be described as functionally redundant, often making the same interactions. Ranking fragments by the number of novel interactions they made, we show that functionally diverse selections of fragments substantially increase the amount of information recovered for unseen targets compared to the amounts recovered by other methods of selection. Using these results, we design small functionally efficient libraries that can give significantly more information about new protein targets than similarly sized structurally diverse libraries. By covering more functional space, we can generate more diverse sets of drug leads.

Journal Keywords: Drug discovery; Molecular interactions; Molecules; Protein structure; Screening assays

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

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

Added On: 14/08/2022 10:59


Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening