ChemMedChem · 2018 · 49 citations · 29 references
PharmacyBiochemistryMedicinal ChemistryCombinatorial ChemistryDrug DiscoveryMolecular RecognitionChemical Library DesignLigand BindingProtein StructureProtein-ligand BindingProtein-ligand RecognitionStructural Basis Of RecognitionCombinatorial Library ScreeningDna-encoded LibrariesDna-encoded Library DesignDna-encoded Library SelectionDna-encoded Library TechnologyEncoded Combinatorial LibrariesEncoded Library ScreeningScaffold-based Library Design
Abstract A DNA‐encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343×492 building blocks. Library screening by affinity capture revealed that for some target proteins, the chemical nature of building blocks dominated the selection results, whereas for other proteins, the central scaffold also crucially contributed to ligand affinity. Molecules based on a 3,5‐bis(aminomethyl)benzoic acid core structure were found to bind human serum albumin with a K d value of 6 n m , while compounds with the same substituents on an equidistant but flexible l ‐lysine scaffold showed 140‐fold lower affinity. A 18 n m tankyrase‐1 binder featured l ‐lysine as linking moiety, while molecules based on d ‐Lysine or (2 S ,4 S )‐amino‐ l ‐proline showed no detectable binding to the target. This work suggests that central scaffolds which predispose the orientation of chemical building blocks toward the protein target may enhance the screening productivity of encoded libraries.
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Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors
E. Wahlberg, T. Karlberg, E. Kouznetsova et al. · Nature Biotechnology · 2012 · 460 citations