title: Tracing binding modes in hit-to-lead optimization: chameleon-like poses of aspartic protease inhibitors.
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.
authors: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 3, 35032 Marburg (Germany).
authors: Maren
authors: M
authors: Kuhnert
authors: Helene
authors: H
authors: Köster
authors: Ruben
authors: R
authors: Bartholomäus
authors: Ah Young
authors: AY
authors: Park
authors: Amir
authors: A
authors: Shahim
authors: Andreas
authors: A
authors: Heine
authors: Holger
authors: H
authors: Steuber
authors: Gerhard
authors: G
authors: Klebe
authors: Wibke E
authors: WE
authors: Diederich
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011480:Protease Inhibitors; D013876:Thiophenes; D016282:Aspartic Acid Endopeptidases; C042466:Endothia aspartic proteinase
keywords: drug design; enzyme inhibitors; ligand-enzyme binding; structure determination; thermal shift assay (TSA)