A DNA‐Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition

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 nm , while compounds with the same substituents on an equidistant but flexible l ‐lysine scaffold showed 140‐fold lower affinity. A 18 nm tankyrase‐1 binder featured l ‐lysine as linking moiety, while molecules based on d ‐Lysine or (2S,4S)‐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.