Abstract
Crystallographic fragment screening (CFS) has become one of the major techniques for screening compounds in the early stages of drug-discovery projects. Following the advances in automation and throughput at modern macromolecular crystallography beamlines, the bottleneck for CFS has shifted from collecting data to organizing and handling the analysis of such projects. The complexity that emerges from the use of multiple methods for processing and refinement and to search for ligands requires an equally sophisticated solution to summarize the output, allowing researchers to focus on the scientific questions instead of on software technicalities. FragMAXapp is the fragment-screening project-management tool designed to handle CFS projects at MAX IV Laboratory. It benefits from the powerful computing infrastructure of large-scale facilities and, as a web application, it is accessible from everywhere.
Highlights
Fragment-based lead discovery utilizes a toolbox of biophysical methods, with X-ray crystallography-based fragment screening (CFS) being the main screening technique to obtain 3D structural information on protein–ligand complexes
With the advent of macromolecular X-ray crystallography (MX) beamlines at fourth-generation photon sources at synchrotron-radiation facilities such as BioMAX at MAX IV Laboratory (Ursby et al, 2020), Manacaat the SIRIUS Light Source (Nascimento, 2020), AMX and FMX at NSLS II (Fuchs et al, 2016) and MASSIF-1, MASSIF-2 and MASSIF-3 at ESRF–EBS, the average data-collection time has been reduced by a factor of ten to less than 40 s for a 360 ! scan
The results from the PROK fragment screening and the apo structures used to build the ground-state model in PanDDA were submitted to the Protein Data Bank (PDB) using the export tool built into FragMAXapp
Summary
Fragment-based lead discovery utilizes a toolbox of biophysical methods, with X-ray crystallography-based fragment screening (CFS) being the main screening technique to obtain 3D structural information on protein–ligand complexes. The massive amount of raw experimental data, its processing and the refinement of all potential structures of protein– ligand complexes, the exploration of bound ligands and the corresponding ligand-binding sites, and meta analysis of the data must be treated integrally This concept was pioneered and first implemented by Astex Therapeutics Ltd (Cambridge, UK; currently part of Astex Pharmaceuticals) within their Pyramid Platform (Davies et al, 2006; Davies & Tickle, 2011). The application guides the user through most stages of the screening experiment, including data processing, analysis, refinement of the models and their deposition in the Protein Data Bank (Berman et al, 2000) Another implementation of the concept was made by EMBL with the web-based Crystallographic Information Management System (CRIMS). At the time of this publication, working versions of FragMAXapp are deployed on BESSY II at the Helmholtz-Zentrum Berlin (Mueller et al, 2015; Wollenhaupt et al, 2021) and at the University of Sao Paulo using data from the SIRIUS Light Source (Noske et al, 2021)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Acta crystallographica. Section D, Structural biology
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
