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 and György M. Keserű ()
Additional contact information
Dávid Bajusz: Medicinal Chemistry Research Group, Research Centre for Natural Sciences
Warren S. Wade: BioBlocks, Inc.
Grzegorz Satała: Maj Institute of Pharmacology Polish Academy of Sciences
Andrzej J. Bojarski: Maj Institute of Pharmacology Polish Academy of Sciences
Janez Ilaš: University of Ljubljana
Jessica Ebner: University of Veterinary Medicine
Florian Grebien: University of Veterinary Medicine
Henrietta Papp: University of Pécs
Ferenc Jakab: University of Pécs
Alice Douangamath: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Daren Fearon: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Frank von Delft: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Marion Schuller: University of Oxford
Ivan Ahel: University of Oxford
Amanda Wakefield: Boston University
Sándor Vajda: Boston University
János Gerencsér: BioBlocks, Inc.
Péter Pallai: BioBlocks, Inc.
György M. Keserű: Medicinal Chemistry Research Group, Research Centre for Natural Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-10

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.

Date: 2021
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DOI: 10.1038/s41467-021-23443-y

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