Fast fragment and compound screening pipeline at the Swiss Light Source.

Autor:	Stegmann DP; Swiss Light Source, Paul Scherrer Institute, Villigen PSI, Switzerland., Steuber J; Institute of Biology, Department of Cellular Microbiology, University of Hohenheim, Stuttgart, Germany., Fritz G; Institute of Biology, Department of Cellular Microbiology, University of Hohenheim, Stuttgart, Germany. Electronic address: guenter.fritz@uni-hohenheim.de., Wojdyla JA; Swiss Light Source, Paul Scherrer Institute, Villigen PSI, Switzerland. Electronic address: justyna.x.wojdyla@gsk.com., Sharpe ME; Swiss Light Source, Paul Scherrer Institute, Villigen PSI, Switzerland. Electronic address: may.sharpe@psi.ch.
Jazyk:	angličtina
Zdroj:	Methods in enzymology [Methods Enzymol] 2023; Vol. 690, pp. 235-284. Date of Electronic Publication: 2023 Sep 12.
DOI:	10.1016/bs.mie.2023.08.005
Abstrakt:	Crystallography-based fragment screening is a highly effective technique employed in structure-based drug discovery to expand the range of lead development opportunities. It allows screening and sorting of weakly binding, low molecular mass fragments, which can be developed into larger high-affinity lead compounds. Technical improvements at synchrotron beamlines, design of innovative libraries mapping chemical space efficiently, effective soaking methods and enhanced data analysis have enabled the implementation of high-throughput fragment screening pipelines at multiple synchrotron facilities. This widened access to CBFS beyond the pharma industry has allowed academic users to rapidly screen large quantities of fragment-soaked protein crystals. The positive outcome of a CBFS campaign is a set of structures that present the three-dimensional arrangement of fragment-protein complexes in detail, thereby providing information on the location and the mode of interaction of bound fragments. Through this review, we provide users with a comprehensive guide that sets clear expectations before embarking on a crystallography-based fragment screening campaign. We present a list of essential pre-requirements that must be assessed, including the suitability of your current crystal system for a fragment screening campaign. Furthermore, we extensively discuss the available methodological options, addressing their limitations and providing strategies to overcome them. Additionally, we provide a brief perspective on how to proceed once hits are obtained. Notably, we emphasize the solutions we have implemented for instrumentation and software development within our Fast Fragment and Compound Screening pipeline. We also highlight third-party software options that can be utilized for rapid refinement and hit assessment. (Copyright © 2023. Published by Elsevier Inc.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu