Structure-based and fragment-based approaches were applied successfully for identifying structurally distinct hits binding to different sub-pockets and conformations of Factor D, a serine protease of the S1 family involved in the amplification loop of the alternative complement pathway. Both approaches represented a valuable strategy to tackle this low ligandable target for which HTS of large compound collections in our hands did not deliver any useful chemical starting points. Two NMR screening efforts were applied against this difficult target: the WaterLOGSY screening of a designed focused target-based library of fragments and the 19F NMR screening of the diverse Novartis library of fluorinated fragments known as LEF (Local Environment of Fluorine). Both methods identified very weak binding affinity fragments which could not be validated by other biophysical techniques. Nevertheless, these initial hits were pursued with chemical modifications and SAR by archive activities with the aim of improving their solubility and potency. Subsequent optimization by merging the key binding elements of these low affinity fragments interacting at different sub-pockets, as elucidated by crystal structures, has resulted in the generation of potent non-covalent orally bioavailable Factor D inhibitors.

Discovery of potent orally bioavailable Factor D inhibitors by exploiting non-validated very weak binding affinity fragments

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.