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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\u2010bis(aminomethyl)benzoic acid core structure were found to bind human serum albumin with a <jats:italic>K<\/jats:italic><jats:sub>d<\/jats:sub> value of 6\u2005n<jats:sc>m<\/jats:sc>, while compounds with the same substituents on an equidistant but flexible <jats:sc>l<\/jats:sc>\u2010lysine scaffold showed 140\u2010fold lower affinity. A 18\u2005n<jats:sc>m<\/jats:sc> tankyrase\u20101 binder featured <jats:sc>l<\/jats:sc>\u2010lysine as linking moiety, while molecules based on <jats:sc>d<\/jats:sc>\u2010Lysine or (2<jats:italic>S<\/jats:italic>,4<jats:italic>S<\/jats:italic>)\u2010amino\u2010<jats:sc>l<\/jats:sc>\u2010proline 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.<\/jats:p>","DOI":"10.1002\/cmdc.201800193","type":"journal-article","created":{"date-parts":[[2018,6,1]],"date-time":"2018-06-01T06:36:51Z","timestamp":1527835011000},"page":"1303-1307","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["A DNA\u2010Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6538-7379","authenticated-orcid":false,"given":"Nicholas","family":"Favalli","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Sciences ETH Z\u00fcrich  Vladimir-Prelog-Weg 4 8093 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Biendl","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences ETH Z\u00fcrich  Vladimir-Prelog-Weg 4 8093 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences ETH Z\u00fcrich  Vladimir-Prelog-Weg 4 8093 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacopo","family":"Piazzi","sequence":"additional","affiliation":[{"name":"Philochem AG  Liebernstrasse 3 8112 Otelfingen Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Sladojevich","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development Roche Innovation Center Basel, F.\u2005Hoffmann-La, Roche Ltd.  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