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

Abstract

Over the last two decades, fragment-based drug discovery (FBDD) has emerged as an effective and efficient method to identify new chemical scaffolds for the development of lead compounds. X-ray crystallography can be used in FBDD as a tool to validate and develop fragments identified as binders by other methods. However, it is also often used with great success as a primary screening technique. In recent years, technological advances at macromolecular crystallography beamlines in terms of instrumentation, beam intensity and robotics have enabled the development of dedicated platforms at synchrotron sources for FBDD using X-ray crystallography. Here, the development of the Fast Fragment and Compound Screening (FFCS) platform, an integrated next-generation pipeline for crystal soaking, handling and data collection which allows crystallography-based screening of protein crystals against hundreds of fragments and compounds, at the Swiss Light Source is reported.

Experiences From Developing Software for Large X-Ray Crystallography-Driven Protein-Ligand Studies

“…The lack of suitable large-scale (publicly-available) processing tools became painfully apparent with the establishment of dedicated synchrotron-based centers for crystallographic fragment screening where hundreds of crystals of the same protein are determined in complex with different compounds ( Collins et al, 2017 ; Lima et al, 2020 ; Cornaciu et al, 2021 ; Douangamath et al, 2021 ; Sharpe and Wojdyla, 2021 ; Wollenhaupt et al, 2021 ; Kaminski et al, 2022 ). As a result, three novel programs—CRIMS, FragMAXapp, and XChemExplorer—became available, which are able to process hundreds of related datasets as part of a single session ( Krojer et al, 2017 ; Cornaciu et al, 2021 ; Lima et al, 2021 ; Wollenhaupt et al, 2021 ).…”

“…These advancements have culminated in the establishment of several publicly accessible centers for crystal-based fragment screening ( Lima et al, 2020 ; Cornaciu et al, 2021 ; Douangamath et al, 2021 ; Wollenhaupt et al, 2021 ; Kaminski et al, 2022 ). The extremes of these setups have now transformed protein crystallography from a structure determination method into another biophysical screening assay technique ( Douangamath et al, 2020 ; Schuller et al, 2021 ; Günther et al, 2021 ).…”

Jungfraujoch: hardware-accelerated data-acquisition system for kilohertz pixel-array X-ray detectors

“…Readout noise, dynamic range, energy coverage and frame rate have been continuously improved with each new generation of detectors. This was experienced at the Paul Scherrer Institute (PSI) with PILATUS (12.5 Hz) and EIGER 16M (133 Hz), introduced in 2007 and 2015, respectively (Broennimann et al, 2006;Dinapoli et al, 2011), which resulted in increasing diffraction resolution with fine slicing (Mueller et al, 2012;Casanas et al, 2016;Fo ¨rster et al, 2019), enabling experimental phasing with native elements (Basu et al, 2019) and fast data collection for fragment-based screening (Thomas et al, 2019;Kaminski et al, 2022) and serial crystallography (Diederichs & Wang, 2017). The upgrades of third-generation synchrotron radiation facilities toward diffraction-limited storage rings like the upcoming Swiss Light Source (SLS) 2.0 will increase source brilliance further, calling for continuous development of detectors and readout systems operated at kilohertz and higher frame rates.…”

SDU – software for high-throughput automated data collection at the Swiss Light Source

“…SLS MX beamlines are served by an in-housedeveloped distributed DA+ software stack, which supports standard rotational single crystal and serial crystal data acquisition and analysis (Wojdyla et al, 2018;Basu et al, 2019). Recent SLS MX hardware developments include the TELL robot with increased dewar capacity and sample exchange speed (Martiel et al, 2020), new TELL gripper design with pin detection, implementation of the fast fragment-and compound-screening pipeline (FFCS) (Kaminski et al, 2022), upgrade of the sample environment top camera and back light, and the installation of SmarGon MCS2 with inhouse smargopolo controls software and calibration routine (Glettig et al, 2022).…”