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Type of publication: Journal Article
Type of document: Full Paper

Year: 2021

Authors: Bajusz, D; Wade, WS; Satała, G; Bojarski, AJ; Ilaš, J; Ebner, J; Grebien, F; Papp, H; Jakab, F; Douangamath, A; Fearon, D; von Delft, F; Schuller, M; Ahel, I; Wakefield, A; Vajda, S; Gerencsér, J; Pallai, P; Keserű, GM

Title: Exploring protein hotspots by optimized fragment pharmacophores.

Source: Nat Commun. 2021; 12(1):3201

Authors Vetmeduni Vienna:

Ebner Jessica
Grebien Florian

Vetmed Research Units
Institute for Medical Biochemistry

Project(s): Common Oncogenic Mechanisms in Multi-Partner Translocation Families in Acute Myeloid Leukemia

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.

Keywords Pubmed: Animals
Cell Survival
Chlorocebus aethiops
Computational Chemistry
Coronavirus 3C Proteaseschemistry
Coronavirus Papain-Like Proteaseschemistry
Crystallography, X-Ray
Databases, Protein
Drug Design
Drug Developmentmethods
Drug Discoverymethods
HEK293 Cells
High-Throughput Screening Assaysmethods
Histone-Lysine N-Methyltransferasechemistry
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
Protein Binding
Receptors, G-Protein-Coupledchemistry
Small Molecule Libraries
Vero Cells

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