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Tracing Binding Modes in Hit‐to‐Lead Optimization: Chameleon‐Like Poses of Aspartic Protease Inhibitors
Authors:Maren Kuhnert  Dr Helene Köster  Dr Ruben Bartholomäus  Dr Ah Young Park  Amir Shahim  Prof?Dr Andreas Heine  Dr Holger Steuber  Prof?Dr Gerhard Klebe  Prof?Dr Wibke E Diederich
Institution:1. Institut für Pharmazeutische Chemie, Philipps‐Universit?t Marburg, Hans‐Meerwein‐Strasse 3, 35032 Marburg (Germany);2. Institut für Pharmazeutische Chemie, Philipps‐Universit?t Marburg, Marbacher Weg 6, 35032 Marburg (Germany);3. LOEWE‐Zentrum für Synthetische Mikrobiologie, Philipps‐Universit?t Marburg, Hans‐Meerwein‐Stra?e, 35032 Marburg (Germany);4. Current address: Bayer Pharma AG, Lead Discovery Berlin ‐ Structural Biology, Müllerstra?e 178, 13353 Berlin (Germany)
Abstract: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.
Keywords:drug design  enzyme inhibitors  ligand–  enzyme binding  structure determination  thermal shift assay (TSA)
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