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A hybrid screening approach for very small fragments - X-ray and Computational Screening on FKBP51
Ist Teil von
Journal of medicinal chemistry, 2020-06, Vol.63 (11), p.5856-5864
Ort / Verlag
United States
Erscheinungsjahr
2020
Link zum Volltext
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
Fragment-based drug discovery (FBDD) deploys efficient sampling of the vast chemical space for hit identification. Libraries are screened biophysically and fragment:protein co-structures are determined by X-ray crystallography. In parallel, computational methods can derive pharmacophore models or screen virtual libraries. We screened 15 very small fragments (VSFs) (HA <= 11) computationally, using site-identification by ligand competitive saturation (SILCS), and experimentally, by X-ray crystallography, to map potential interaction sites on the FKBP51 FK1 domain. We identified three hot spots and obtained 6 X-ray co-structures, giving a hit rate of 40%. SILCS FragMaps overlapped with X-ray structures. The compounds had millimolar affinities as determined by
N HSQC NMR. VSFs identified the same interactions as known FK1 binder and provide new chemical starting points. We propose a hybrid screening strategy starting with SILCS, followed by a pharmacophore-derived X-ray screen and
N HSQC NMR based KD determination to rapidly identify hits and their binding poses.