title: Protein-Templated Fragment Ligations-From Molecular Recognition to Drug Discovery.
abstract: Protein-templated fragment ligation is a novel concept to support drug discovery and can help to improve the efficacy of protein ligands. Protein-templated fragment ligations are chemical reactions between small molecules ("fragments") utilizing a protein's surface as a reaction vessel to catalyze the formation of a protein ligand with increased binding affinity. The approach exploits the molecular recognition of reactive small-molecule fragments by proteins both for ligand assembly and for the identification of bioactive fragment combinations. In this way, chemical synthesis and bioassay are integrated in one single step. This Review discusses the biophysical basis of reversible and irreversible fragment ligations and gives an overview of the available methods to detect protein-templated ligation products. The chemical scope and recent applications as well as future potential of the concept in drug discovery are reviewed.
authors.affiliation: Freie Universität Berlin, Medicinal Chemistry, Königin-Luise-Strasse 2+4, Berlin, 14195, Germany.
authors.forename: Mike
authors.initials: M
authors.lastname: Jaegle
authors.affiliation: Freie Universität Berlin, Medicinal Chemistry, Königin-Luise-Strasse 2+4, Berlin, 14195, Germany.
authors.forename: Ee Lin
authors.initials: EL
authors.lastname: Wong
authors.affiliation: Freie Universität Berlin, Medicinal Chemistry, Königin-Luise-Strasse 2+4, Berlin, 14195, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Tauber
authors.affiliation: Freie Universität Berlin, Medicinal Chemistry, Königin-Luise-Strasse 2+4, Berlin, 14195, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Nawrotzky
authors.affiliation: Freie Universität Berlin, Medicinal Chemistry, Königin-Luise-Strasse 2+4, Berlin, 14195, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Arkona
authors.affiliation: Freie Universität Berlin, Medicinal Chemistry, Königin-Luise-Strasse 2+4, Berlin, 14195, Germany.
authors.forename: Jörg
authors.identifier: 0000-0001-6678-3165
authors.initials: J
authors.lastname: Rademann
mesh_terms: D055592:Biophysical Phenomena; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*
chemical_list: D008024:Ligands; D011506:Proteins
keywords: dynamic covalent chemistry; fragment-based drug discovery; high-throughput screening; molecular recognition; protein-templated reactions