Fragments in Drug Discovery

Carbohydrate–protein interactions are key for cell–cell and host–pathogen recognition, but their hydrophilic nature makes the development of drug-like inhibitors a challenge. Here, screening of fragment libraries identifies metal-binding pharmacophores as novel scaffolds for the inhibition of Ca²⁺-dependent carbohydrate–protein interactions.

The AAA+ ATPase p97 protein is thought to be a potential anticancer target, but direct targeting on its ATPase function has not proven to be a successful strategy in clinical trials due to lack of selectivity. Here, the authors use biolayer interferometry-based fragment screening to identify ligands for the development of protein-protein interaction inhibitors by targeting the SHP-motif as a cofactor binding site in the N-domain of p97.

Dual-pharmacophore DNA-Encoded Libraries (DELs) can generate large libraries, but linker optimisation is challenging. Here, the authors report a trio-pharmacophore DEL (T-DEL) for both de novo fragment identification and linker optimization of known fragment pairs.

Peptide fragments derived from the interfaces of protein-protein interactions (PPIs) provide useful templates for designing small molecule PPI inhibitors. Here, the authors utilize the multivalency of an MdmX-binding p53 peptide to develop a weak inhibitor of MdmX into potent Mdm2/MdmX inhibitors.

Fragment-based drug design is an effective approach to identifying potential binders for a given target protein, but accurately capturing changes in affinity associated with a given set of chemical modifications remains challenging. Here, the authors evaluate the use of absolute binding free energy calculations in guiding fragment optimisation decisions, finding that such calculations can usefully guide fragment elaborations to maximise affinity.

Molecular dynamics (MD) simulations play an important role in assessing allosteric effects to assist fragment-based screening, however, fully allosteric modulation remains challenging via standard unbiased MD simulations. Here, the authors develop steered MD simulations combined with a Markov State Modeling protocol to assess certain protein conformations that are important for allosteric binding.

Interleukin-1β is a pro-inflammatory cytokine of medical importance. Here the authors describe the discovery of a low-molecular weight compound that antagonizes hIL-1β function in cells, demonstrating the relevance of this discovery for future development of hIL-1β directed therapeutics.