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. 2021 Jun 1;77(Pt 6):799-808.
doi: 10.1107/S2059798321003818. Epub 2021 May 14.

FragMAXapp: crystallographic fragment-screening data-analysis and project-management system

Gustavo M A Lima  1 , Elmir Jagudin  1 , Vladimir O Talibov  1 , Laila S Benz  2 , Costantino Marullo  1 , Tatjana Barthel  3 , Jan Wollenhaupt  3 , Manfred S Weiss  3 , Uwe Mueller  3
Affiliations

FragMAXapp: crystallographic fragment-screening data-analysis and project-management system

Gustavo M A Lima et al. Acta Crystallogr D Struct Biol. .

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.

Keywords: drug discovery; fragment screening; fragment-based lead discovery; high-throughput data analysis; protein crystallography.

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Figures

Figure 1
Figure 1
(a) FragMAXapp schematic diagram. The diagram shows connected steps and the relationship between each interaction, process and database entry. It is divided into three groups based on where the actions take place. Steps coloured dark grey use the HTML interface for interaction, light grey steps are tasks performed in the experimental laboratory and chequered steps are tasks performed in the background (for example HPC jobs). (b) FragMAXapp development design. Processing jobs are controlled by a Slurm workload manager installed in the front end of the MAX IV HPC. The three servers and the database necessary for FragMAXapp are deployed inside a Docker container inside a virtual machine, ensuring performance and stability of the installation. The user interface is designed using HTML5, CSS3 and JavaScript, which are available in all modern browsers.
Figure 2
Figure 2
FragMAXapp Project Overview page. It displays information about the data collection and the status of data processing. A full representation of the user interface is available in Supplementary Fig. S2.
Figure 3
Figure 3
FragMAXapp sample-management page. The 2D representations of the ligands are generated using RDKit, while 3D representations are displayed using the 3Dmol library. This page allows additions or updates to the sample definitions within the project. A full representation of the user interface is available in Supplementary Fig. S3.
Figure 4
Figure 4
FragMAXapp Data Analysis page. An extensive selection of software and pipelines is available to analyse the data. A full representation of the user interface is available in Supplementary Fig. S4.
Figure 5
Figure 5
FragMAXapp density viewer. The viewer features unexplained blobs and navigation between the models, information about the result, log access, ligand navigation for automatic ligand-fitting results and structure scores. The density viewer is based on UglyMOL. A full representation of the user interface is available in Supplementary Fig. S5.
Figure 6
Figure 6
Proteinase K sites numbered from 1 to 7 as identified by PanDDA analysis.
Figure 7
Figure 7
Automated ligand-searching comparison. The LigandFit and Rhofit columns take the highest scored ligand from each method. The PanDDA column shows ligands that were manually modelled. Ligands with a different binding site for different methods are annotated. All structures and density maps are publicly available.
See this image and copyright information in PMC

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