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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Query-guided protein–protein interaction inhibitor discovery Sergio Celis , Fruzsina Hobor , Thomas James , Gail J. Bartlett , Amaurys A. Ibarra , Deborah K. Shoemark , Zsofia Hegedus , Kristina Hetherington , Derek N. Woolfson , Richard B. Sessions , Thomas A. Edwards , David M. Andrews , Adam Nelson , Andrew J. Wilson Chemical Science 19 DOI: 10.1039/D1SC00023C Diamond Proposal Number(s): [19248] Open Access Show Abstract ▼ Abstract: Protein–protein interactions (PPIs) are central to biological mechanisms, and can serve as compelling targets for drug discovery. Yet, the discovery of small molecule inhibitors of PPIs remains challenging given the large and typically shallow topography of the interacting protein surfaces. Here, we describe a general approach to the discovery of orthosteric PPI inhibitors that mimic specific secondary protein structures. Initially, hot residues at protein–protein interfaces are identified in silico or from experimental data, and incorporated into secondary structure-based queries. Virtual libraries of small molecules are then shape-matched against the queries, and promising ligands docked to target proteins. The approach is exemplified experimentally using two unrelated PPIs that are mediated by an α-helix (p53/hDM2) and a β-strand (GKAP/SHANK1-PDZ). In each case, selective PPI inhibitors are discovered with low μM activity as determined by a combination of fluorescence anisotropy and 1H–15N HSQC experiments. In addition, hit expansion yields a series of PPI inhibitors with defined structure–activity relationships. It is envisaged that the generality of the approach will enable discovery of inhibitors of a wide range of unrelated secondary structure-mediated PPIs.	Mar 2021
I03-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Identification of β-strand mediated protein–protein interaction inhibitors using ligand-directed fragment ligation Zsofia Hegedus , Fruzsina Hobor , Deborah K. Shoemark , Sergio Celis , Lu-Yun Lian , Chi H. Trinh , Richard B. Sessions , Thomas A. Edwards , Andrew J. Wilson Chemical Science 153 DOI: 10.1039/D0SC05694D Diamond Proposal Number(s): [19248] Open Access Show Abstract ▼ Abstract: β-Strand mediated protein–protein interactions (PPIs) represent underexploited targets for chemical probe development despite representing a significant proportion of known and therapeutically relevant PPI targets. β-Strand mimicry is challenging given that both amino acid side-chains and backbone hydrogen-bonds are typically required for molecular recognition, yet these are oriented along perpendicular vectors. This paper describes an alternative approach, using GKAP/SHANK1 PDZ as a model and dynamic ligation screening to identify small-molecule replacements for tranches of peptide sequence. A peptide truncation of GKAP functionalized at the N- and C-termini with acylhydrazone groups was used as an anchor. Reversible acylhydrazone bond exchange with a library of aldehyde fragments in the presence of the protein as template and in situ screening using a fluorescence anisotropy (FA) assay identified peptide hybrid hits with comparable affinity to the GKAP peptide binding sequence. Identified hits were validated using FA, ITC, NMR and X-ray crystallography to confirm selective inhibition of the target PDZ-mediated PPI and mode of binding. These analyses together with molecular dynamics simulations demonstrated the ligands make transient interactions with an unoccupied basic patch through electrostatic interactions, establishing proof-of-concept that this unbiased approach to ligand discovery represents a powerful addition to the armory of tools that can be used to identify PPI modulators.	Jan 2021

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