6TXX

CRYSTAL STRUCTURE OF HUMAN FKBP51 FK1 DOMAIN A19T MUTANT IN COMPLEX WITH SAFit2

Summary for 6TXX

• Entry DOI: 10.2210/pdb6txx/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase FKBP5, (1R)-3-(3,4-dimethoxyphenyl)-1-{3-[2-(morpholin-4-yl)ethoxy]phenyl}propyl (2S)-1-[(2S)-2-[(1S)-cyclohex-2-en-1-yl]-2-(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carboxylate (3 entities in total)
• Functional Keywords: ppiase, isomerase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 28853.13

Authors

Fiegen, D.,Draxler, S.W. (deposition date: 2020-01-14, release date: 2020-05-27, Last modification date: 2024-01-24)

Primary citation

Draxler, S.W.,Bauer, M.,Eickmeier, C.,Nadal, S.,Nar, H.,Rangel Rojas, D.,Seeliger, D.,Zeeb, M.,Fiegen, D.
Hybrid Screening Approach for Very Small Fragments: X-ray and Computational Screening on FKBP51.
J.Med.Chem., 63:5856-5864, 2020

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 ≤ 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.

PubMed: 32420743
DOI: 10.1021/acs.jmedchem.0c00120

Experimental method

X-RAY DIFFRACTION (2.1 Å)