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- Weiss, Manfred S., et al.
(författare)
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Of problems and opportunities—How to treat and how to not treat crystallographic fragment screening data
- 2022
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Ingår i: Protein Science. - : Wiley. - 0961-8368 .- 1469-896X. ; 31:9
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Tidskriftsartikel (refereegranskat)abstract
- In their recent commentary in Protein Science, Jaskolski et al. analyzed three randomly picked diffraction data sets from fragment-screening group depositions from the PDB and, based on that, they claimed that such data are principally problematic. We demonstrate here that if such data are treated properly, none of the proclaimed criticisms persist.
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- Radeva, Nedyalka, et al.
(författare)
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Active Site Mapping of an Aspartic Protease by Multiple Fragment Crystal Structures : Versatile Warheads to Address a Catalytic Dyad
- 2016
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:21, s. 9743-9759
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Tidskriftsartikel (refereegranskat)abstract
- Crystallography is frequently used as follow-up method to validate hits identified by biophysical screening cascades. The capacity of crystallography to directly screen fragment libraries is often underestimated, due to its supposed low-throughput and need for high-quality crystals. We applied crystallographic fragment screening to map the protein-binding site of the aspartic protease endothiapepsin by individual soaking experiments. Here, we report on 41 fragments binding to the catalytic dyad and adjacent specificity pockets. The analysis identifies already known warheads but also reveals hydrazide, pyrazole, or carboxylic acid fragments as novel functional groups binding to the dyad. A remarkable swapping of the S1 and S1′ pocket between structurally related fragments is explained by either steric demand, required displacement of a well-bound water molecule, or changes of trigonal-planar to tetrahedral geometry of an oxygen functional group in a side chain. Some warheads simultaneously occupying both S1 and S1′ are promising starting points for fragment-growing strategies.
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- Schiebel, Johannes, et al.
(författare)
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High-Throughput Crystallography : Reliable and Efficient Identification of Fragment Hits
- 2016
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Ingår i: Structure. - : Elsevier BV. - 0969-2126. ; 24:8, s. 409-1398
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Tidskriftsartikel (refereegranskat)abstract
- Today the identification of lead structures for drug development often starts from small fragment-like molecules raising the chances to find compounds that successfully pass clinical trials. At the heart of the screening for fragments binding to a specific target, crystallography delivers structural information essential for subsequent drug design. While it is common to search for bound ligands in electron densities calculated directly after an initial refinement cycle, we raise the important question whether this strategy is viable for fragments characterized by low affinities. Here, we describe and provide a collection of high-quality diffraction data obtained from 364 protein crystals treated with diverse fragments. Subsequent data analysis showed that ∼25% of all hits would have been missed without further refining the resulting structures. To enable fast and reliable hit identification, we have designed an automated refinement pipeline that will inspire the development of optimized tools facilitating the successful application of fragment-based methods.
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- Wollenhaupt, Jan, et al.
(författare)
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F2X-Universal and F2X-Entry : Structurally Diverse Compound Libraries for Crystallographic Fragment Screening
- 2020
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Ingår i: Structure. - : Elsevier BV. - 0969-2126. ; 28, s. 694-706
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Tidskriftsartikel (refereegranskat)abstract
- Crystallographic fragment screening (CFS) provides excellent starting points for projects concerned with drug discovery or biochemical tool compound development. One of the fundamental prerequisites for effective CFS is the availability of a versatile fragment library. Here, we report on the assembly of the 1,103-compound F2X-Universal Library and its 96-compound sub-selection, the F2X-Entry Screen. Both represent the available fragment chemistry and are highly diverse in terms of their 3D-pharmacophore variations. Validation of the F2X-Entry Screen in CFS campaigns using endothiapepsin and the Aar2/RNaseH complex yielded hit rates of 30% and 21%, respectively, and revealed versatile binding sites. Dry presentation of the libraries allows CFS campaigns to be carried out with or without the co-solvent DMSO present. Most of the hits in our validation campaigns could be reproduced also in the absence of DMSO. Consequently, CFS can be carried out more efficiently and for a wider range of conditions and targets.
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