Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source

作者： Alice Douangamath*1,2, Ailsa Powell*1,2, Daren Fearon*1,2, Patrick M. Collins1,2, Romain Talon1,2,3, Tobias Krojer3,4, Rachael Skyner1,2, Jose Brandao-Neto1,2, Louise Dunnett1,2, Alexandre Dias1,2, Anthony Aimon1,2,3, Nicholas M. Pearce1,3, Conor Wild3,5, Tyler Gorrie-Stone1, Frank von Delft1,2,3,4,6 1Diamond Light Source Ltd, Harwell Science and Innovation Campus, 2Research Complex at Harwell, Harwell Science and Innovation Campus, 3Structural Genomics Consortium,University of Oxford, 4Centre for Medicines Discovery,University of Oxford, 5Oxford Protein Informatics Group, Department of Statistics,Oxford University, 6Department of Biochemistry,University of Johannesburg

简介：

Overview

This paper describes the complete XChem process for crystal-based fragment screening, detailing the steps from access application to data dissemination. The XChem Facility at Diamond Light Source enhances fragment-based drug discovery through efficient X-ray crystallography.

Key Study Components

Area of Science

• Fragment-based drug discovery (FBDD)
• X-ray crystallography
• Structural biology

Background

• Fragment-based drug discovery is a strategy for lead discovery.
• X-ray crystallography provides structural insights into molecular interactions.
• Traditional soaking methods have limitations that XChem addresses.
• The XChem platform has shown resilience during the COVID-19 pandemic.

Purpose of Study

• To document the XChem pipeline protocols from sample preparation to final structures.
• To demonstrate the efficiency of the XChem platform for fragment screening.
• To highlight the impact of crystallographic fragment screening on drug discovery.

Methods Used

• Selection of crystals and compounds for screening.
• Use of acoustic dispensers for solution dispensing.
• Harvesting crystals using semi-automatic devices.
• Data analysis through XChem Explorer and Panda software.

Main Results

• Successful campaigns yield three-dimensional maps of interaction sites.
• Documented uptake of the user program from 2015 to 2019.
• Identification of potential allosteric sites and active sites on proteins.
• Streamlined protocols enable broader scientific community access.

Conclusions

• The XChem pipeline significantly enhances fragment screening efficiency.
• Crystallographic fragment screening complements other biophysical techniques.
• Advancements in the XChem platform support ongoing drug discovery efforts.

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