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Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength)	Water networks as hydrophobic recognition motifs in proteins Serena G. Piticchio , Miriam Martinez-Cartro , Salvatore Scaffidi , Sergio Rodríguez-Arévalo , Andrea Bagán , Ainoa Sánchez-Arfelis , Sarah Picaud , Tobias Krojer , Panagis Filippakopoulos , Carmen Escolano , Xavier Barril , Frank Von Delft Angewandte Chemie International Edition DOI: 10.1002/anie.202521138 Diamond Proposal Number(s): [19301] Open Access Show Abstract ▼ Abstract: The hydrophobic effect is a central force in molecular recognition, typically attributed to the ordering of water molecules around apolar groups. Hydrophobic interaction sites on proteins are therefore readily predicted based on surface polarity. Yet, in the bromodomain-containing protein 4 (BRD4), a well-known hydrophobic hot spot is paradoxically lined by a network of water molecules. Here we combine binding assays, structural data, molecular dynamics, and free-energy calculations to resolve this apparent contradiction. We show that the water network functions as a hydrophobic recognition motif that cannot accommodate polar groups without disruption. Instead, as the protein pre-organizes the water network, apolar groups can bind with minimal entropic cost. In turn, they reinforce the surrounding hydrogen-bond network, limiting the mobility of the entire protein–water assembly. With this perspective, we identify water networks potentially functioning as hydrophobic motifs in other pharmacological targets, revealing a general but overlooked recognition element with broad implications in drug discovery and protein design.	Nov 2025
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of novel BRD4 ligand scaffolds by automated navigation of the fragment chemical space Serena G. Piticchio , Miriam Martinez-Cartro , Salvatore Scaffidi , Moira Rachman , Sergio Rodriguez-Arevalo , Ainoa Sanchez-Arfelis , Carmen Escolano , Sarah Picaud , Tobias Krojer , Panagis Filippakopoulos , Frank Von Delft , Carles Galdeano , Xavier Barril Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c01108 Diamond Proposal Number(s): [15433, 19301] Show Abstract ▼ Abstract: Fragment-based drug discovery (FBDD) is a very effective hit identification method. However, the evolution of fragment hits into suitable leads remains challenging and largely artisanal. Fragment evolution is often scaffold-centric, meaning that its outcome depends crucially on the chemical structure of the starting fragment. Considering that fragment screening libraries cover only a small proportion of the corresponding chemical space, hits should be seen as probes highlighting privileged areas of the chemical space rather than actual starting points. We have developed an automated computational pipeline to mine the chemical space around any specific fragment hit, rapidly finding analogues that share a common interaction motif but are structurally novel and diverse. On a prospective application on the bromodomain-containing protein 4 (BRD4), starting from a known fragment, the platform yields active molecules with nonobvious scaffold changes. The procedure is fast and inexpensive and has the potential to uncover many hidden opportunities in FBDD.	Dec 2021

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