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Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength)	Exploring protein hotspots by optimized fragment pharmacophores Dávid Bajusz , Warren S. Wade , Grzegorz Satała , Andrzej J. Bojarski , Janez Ilaš , Jessica Ebner , Florian Grebien , Henrietta Papp , Ferenc Jakab , Alice Douangamath , Daren Fearon , Frank Von Delft , Marion Schuller , Ivan Ahel , Amanda Wakefield , Sándor Vajda , János Gerencsér , Péter Pallai , György M. Keserű Nature Communications 12 DOI: 10.1038/s41467-021-23443-y Diamond Proposal Number(s): [27001, 18145, 27963] Open Access Show Abstract ▼ Abstract: Fragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pharmacophores, the most general concept of representing drug-target interactions with the theory of protein hotspots, to develop a design protocol for fragment libraries. The SpotXplorer approach compiles small fragment libraries that maximize the coverage of experimentally confirmed binding pharmacophores at the most preferred hotspots. The efficiency of this approach is demonstrated with a pilot library of 96 fragment-sized compounds (SpotXplorer0) that is validated on popular target classes and emerging drug targets. Biochemical screening against a set of GPCRs and proteases retrieves compounds containing an average of 70% of known pharmacophores for these targets. More importantly, SpotXplorer0 screening identifies confirmed hits against recently established challenging targets such as the histone methyltransferase SETD2, the main protease (3CLPro) and the NSP3 macrodomain of SARS-CoV-2.	May 2021

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I04-1-Macromolecular Crystallography (fixed wavelength)

Exploring protein hotspots by optimized fragment pharmacophores