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Exploring protein hotspots by optimized fragment pharmacophores

DOI: 10.1038/s41467-021-23443-y DOI Help

Authors: Dávid Bajusz (Research Centre for Natural Sciences, Budapest) , 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, Vienna) , Florian Grebien (University of Veterinary Medicine, Vienna) , Henrietta Papp (University of Pécs) , Ferenc Jakab (University of Pécs) , Alice Douangamath (Diamond Light Source, Research Complex at Harwell) , Daren Fearon (Diamond Light Source; Research Complex at Harwell) , Frank Von Delft (Diamond Light Source; Research Complex at Harwell; Structural Genomics Consortium, University of Oxford; University of Johannesburg) , 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 (Research Centre for Natural Sciences, Budapest)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: May 2021
Diamond Proposal Number(s): 27001 , 18145 , 27963

Open Access Open Access

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.

Journal Keywords: Chemical libraries; Drug discovery and development

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 31/05/2021 08:28


Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening