Download MendeleyHybrid Screening Approach for Very Small Fragments: X-ray and Computational Screening on FKBP51.
Draxler, S.W., Bauer, M., Eickmeier, C., Nadal, S., Nar, H., Rangel Rojas, D., Seeliger, D., Zeeb, M., Fiegen, D.(2020) J Med Chem 63: 5856-5864
- PubMed: 32420743
- DOI: https://doi.org/10.1021/acs.jmedchem.0c00120
- Primary Citation of Related Structures:
6TX4, 6TX5, 6TX6, 6TX7, 6TX8, 6TX9, 6TXX - PubMed Abstract:
Fragment-based drug discovery (FBDD) permits 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 ¡Ü 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 15 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 15 N HSQC NMR based KD determination to rapidly identify hits and their binding poses.
Organizational Affiliation:
Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstra?e 65, 88397 Biberach, Germany.
