Tracing Binding Modes in Hit-to-Lead Optimization: Chameleon-Like Poses of Aspartic Protease Inhibitors

• Published in: Angewandte Chemie International Edition 2015-02, Vol.54 (9), p.2849-2853
• Main Authors: Kuhnert, Maren, Köster, Helene, Bartholomäus, Ruben, Park, Ah Young, Shahim, Amir, Heine, Andreas, Steuber, Holger, Klebe, Gerhard, Diederich, Wibke E.
• Format: Article
• Language: English
• Subjects: Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemical synthesis; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - metabolism; Aspartic Acid Endopeptidases - pharmacology; Binding; Binding Sites - drug effects; Decision making; Decoration; Dose-Response Relationship, Drug; drug design; enzyme inhibitors; Indicators; Inhibitors; ligand-enzyme binding; Models, Molecular; Molecular Structure; Optimization; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Scaffolds; structure determination; Structure-Activity Relationship; thermal shift assay (TSA); Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; X-rays
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201411206

Successful lead optimization in structure‐based drug discovery depends on the correct deduction and interpretation of the underlying structure–activity relationships (SAR) to facilitate efficient decision‐making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)‐validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X‐ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well‐established surrogate for e.g. renin and β‐secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation. Changing poses: The optimization of lead structures relies on the systematic variation of the substituents decorating a given hit scaffold which is based on one binding pose that is supposed to be invariable. For a given core scaffold, only minor chemical variations were found to result in four different binding modes. An indicative metric is suggested to assess candidates that qualify for structural revalidation.