Crystallographic Fragment Screening at BESSY II — From Hits to Improved Binders


Thu, 24 Nov 2022, 16:00 CET (Berlin)

Dr. Jan Wollenhaupt, Helmholtz-Zentrum Berlin für Materialien und Energie, Macromolecular Crystallography (HZB-MX), Germany

Crystallographic Fragment Screening at BESSY II — From Hits to Improved Binders

When fragment screening is carried out using X-ray crystallography it reveals the 3D-position of the fragment hits inside the protein’s binding site. This additional information of the fragment’s position is highly valuable for further improvement of the usual “low-affinity fragments” to create binders of higher potency. By combining fragment-based and structure-based drug discovery, binders of higher potency can be achieved.

At the macromolecular crystallography (MX) beamlines at BESSY II, a dedicated workflow was established for the user community. It fosters efficient and convenient screening[1] and is based on several unique developments: First, the very diverse F2X fragment libraries that deliver high hit rates, mostly in the range of 20-25%.[2,3] Second, tools like the EasyAccess Frame ensure fast and comfortable crystal soaking and harvesting.[4] After data collection at the state-of-the-art MX beamlines at BESSY II, data analysis is highly automated and conveniently interfaced via the FragMAXapp setup at HZB.[5] FragMAXapp enables automatic data treatment using a number of pipelines, including the HZB-developments XDSAPP for automatic processing and fspipeline for automatic refinement.[6,7] As a final step, improved methodologies like PanDDA are applied for the best identification of the fragments in the electron density.[8]

Beyond efficient MX-based screening, HZB also offers methods of hit evolution to higher potency via fragment growing. In HZB’s Frag4Lead workflow the 3D-information of the crystallographic hits are used as an anchor for virtual pre-screening of suitable candidates from chemical catalogs.[9] This way, the first fragment growing step can be achieved without the need for custom synthesis and minimal virtual-screening expertise. Jan and team successfully employed Frag4Lead to advance fragment hits to single-digit micromolar binders in one step and shall report about this.

[1]    Wollenhaupt, J. et al. J. Vis. Exp. 2021, 62208 (2021).

[2]    Wollenhaupt, J. et al.. Structure 28, 694-706.e5 (2020).

[3]    Barthel, T. et al. J. Med. Chem. (2022).

[4]    Barthel, T. et al. J. Appl. Cryst. 54, 376–382 (2021).

[5]    Lima, G. M. A. et al. Acta Cryst. D 77, 799–808 (2021).

[6]    Sparta, K. et al. J. Appl. Cryst. 49, 1085-1092 (2016).

[7]    Schiebel, J. et al. Structure 24, 1398–1409 (2016).

[8]    Pearce, N. M., et al. Nature Comm. 8, 15123 (2017).

[9]    Metz, A. et al. Acta Cryst. D 77, 1168–1182 (2021).

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