Achieving efficient fragment screening at XChem facility at Diamond Light Source

DOI: 10.3791/62414

Authors: Alice Douangamath (Diamond Light Source; Research Complex at Harwell) , Alisa Powell (Diamond Light Source; Research Complex at Harwell) , Daren Fearon (Diamond Light Source; Research Complex at Harwell) , Patrick M. Collins (Diamond Light Source; Research Complex at Harwell) , Romain Talon (Diamond Light Source; Research Complex at Harwell; Structural Genomics Consortium, University of Oxford) , Tobias Krojer (Structural Genomics Consortium, University of Oxford) , Rachael Skyner (Diamond Light Source; Research Complex at Harwell) , Jose Brandao-Neto (Diamond Light Source; Research Complex at Harwell) , Louise Dunnett (Diamond Light Source; Research Complex at Harwell) , Alexandre Dias (Diamond Light Source; Research Complex at Harwell) , Anthony Aimon (Diamond Light Source; Research Complex at Harwell; Structural Genomics Consortium, University of Oxford) , Nicholas M. Pearce (Diamond Light Source; Structural Genomics Consortium, University of Oxford) , Conor Wild (Structural Genomics Consortium, University of Oxford) , Tyler J. Gorrie-Stone (Diamond Light Source) , Frank Von Delft (Diamond Light Source; Research Complex at Harwell; Structural Genomics Consortium, University of Oxford; University of Johannesburg)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Visualized Experiments

State: Published (Approved)
Published: May 2021

Abstract: In fragment-based drug discovery, hundreds or often thousands of compounds smaller than ~300 Da are tested against the protein of interest to identify chemical entities that can be developed into potent drug candidates. Since the compounds are small, interactions are weak, and the screening method must therefore be highly sensitive; moreover, structural information tends to be crucial for elaborating these hits into lead-like compounds. Therefore, protein crystallography has always been a gold-standard technique, yet historically too challenging to find widespread use as a primary screen. Initial XChem experiments were demonstrated in 2014 and then trialed with academic and industrial collaborators to validate the process. Since then, a large research effort and significant beamtime have streamlined sample preparation, developed a fragment library with rapid follow-up possibilities, automated and improved the capability of I04-1 beamline for unattended data collection, and implemented new tools for data management, analysis and hit identification. XChem is now a facility for large-scale crystallographic fragment screening, supporting the entire crystals-to-deposition process, and accessible to academic and industrial users worldwide. The peer-reviewed academic user program has been actively developed since 2016, to accommodate projects from as broad a scientific scope as possible, including well-validated as well as exploratory projects. Academic access is allocated through biannual calls for peer-reviewed proposals, and proprietary work is arranged by Diamond's Industrial Liaison group. This workflow has already been routinely applied to over a hundred targets from diverse therapeutic areas, and effectively identifies weak binders (1%-30% hit rate), which both serve as high-quality starting points for compound design and provide extensive structural information on binding sites. The resilience of the process was demonstrated by continued screening of SARS-CoV-2 targets during the COVID-19 pandemic, including a 3-week turn-around for the main protease.

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: XChem
Instruments: NONE-No attached Diamond beamline

Added On: 02/06/2021 13:24

Documents:
jove-protocol-62414-achieving-efficient-fragment-screening-at-xchem-facility-at-diamond.pdf

Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening