Binding-Site Compatible Fragment Growing Applied to the Design of β-Adrenergic Receptor Ligands.

TitleBinding-Site Compatible Fragment Growing Applied to the Design of β-Adrenergic Receptor Ligands.
Publication TypeJournal Article
Year of Publication2018
AuthorsChevillard, F., Rimmer H., Betti C., Pardon E., Ballet S., van Hilten N., Steyaert J., Diederich W. E., and Kolb P.
JournalJ Med Chem
Date Published2018 Feb 08

Fragment-based drug discovery is intimately linked to fragment extension approaches that can be accelerated using software for de novo design. Although computers allow for the facile generation of millions of suggestions, synthetic feasibility is however often neglected. In this study we computationally extended, chemically synthesized, and experimentally assayed new ligands for the β-adrenergic receptor (βAR) by growing fragment-sized ligands. In order to address the synthetic tractability issue, our in silico workflow aims at derivatized products based on robust organic reactions. The study started from the predicted binding modes of five fragments. We suggested a total of eight diverse extensions that were easily synthesized, and further assays showed that four products had an improved affinity (up to 40-fold) compared to their respective initial fragment. The described workflow, which we call "growing via merging" and for which the key tools are available online, can improve early fragment-based drug discovery projects, making it a useful creative tool for medicinal chemists during structure-activity relationship (SAR) studies.

Alternate JournalJ. Med. Chem.
PubMed ID29364664
Research group: