New Paper – FragLite and PepLite screening aids early-stage ligand discovery

J. Med. Chem. 2022, 65, 15416-15432

https://doi.org/10.1021/acs.jmedchem.2c01357

https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.2c01357

Gemma Davison, Mathew P. Martin, Shannon Turberville, Selma Dormen, Richard Heath, Amy B. Heptinstall, Marie Lawson, Duncan C. Miller, Yi Min Ng, James N. Sanderson, Ian Hope, Daniel J. Wood, Céline Cano, Jane A. Endicott, Ian R. Hardcastle, Martin E. M. Noble,* and Michael J. Waring*

One of the most effective ways of establishing sites of interactions between proteins and their natural or unnatural ligands is by compound screening and structural biology. In a bid to circumvent the need for extensive testing of druglike or fragment-like libraries, we recently described the use of FragLites. Comprising a small set of very simple compounds, FragLites display hydrogen-bonding motifs, specifically proximal combinations of two hydrogen-bonding groups, designed to permit the co-operative formation of hydrogen bonds.

FragLite mapping is comparable to a full fragment screen in identifying ligand binding sites on proteins. Analysis of FragLite binding identifies key hydrogen bonding interactions that can be exploited to generate compounds of leadlike potency and could guide further hit generation activities.

Although the FragLite concept was illustrated with mapping of CDK2, we wished to further develop this approach in order to explore a wider range of proteins. This work demonstrates the utility of FragLites in establishing druggability, illustrated by the two bromodomain proteins, BRD4 and ATAD2. The FragLite set was extended with analogous compounds derived from amino acids (termed PepLites) that mimic the interactions of peptides. Hence, this shows that FragLites and PepLites could be used in isolation or in conjunction with other hit-finding activities to develop drug candidates or chemical probes for novel targets.

The work described 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.

Last modified: Mon, 19 Dec 2022 17:34:39 GMT