FragMAX: the fragment-screening platform at the MAX IV Laboratory.

Gustavo M A Lima,Tove Sjögren,Céleste Sele,Elmir Jagudin,Vladimir O Talibov,Derek T Logan,Wolfgang Knecht,Maria Nyblom,Uwe Mueller

doi:10.1107/s205979832000889x

Abstract

Advances in synchrotron storage rings and beamline automation have pushed data-collection rates to thousands of data sets per week. With this increase in throughput, massive projects such as in-crystal fragment screening have become accessible to a larger number of research groups. The quality of support offered at large-scale facilities allows medicinal chemistry-focused or biochemistry-focused groups to supplement their research with structural biology. Preparing the experiment, analysing multiple data sets and prospecting for interesting complexes of protein and fragments require, for both newcomers and experienced users, efficient management of the project and extensive computational power for data processing and structure refinement. Here, FragMAX, a new complete platform for fragment screening at the BioMAX beamline of the MAX IV Laboratory, is described. The ways in which users are assisted in X-ray-based fragment screenings and in which the fourth-generation storage ring available at the facility is best exploited are also described.

Highlights

Fragments are small organic molecules, often with a molecular weight (MW) of below 200 Da, which can form weak but still specific interactions with proteins
The platform benefits vastly from the extremely brilliant X-ray beam provided by the fourth-generation 3 GeV storage ring at the MAX IV Laboratory and the state-of-art instrumentation of the BioMAX beamline, with high-throughput data collection and automation of data processing
The proteins used for comparing the different data-analysis strategies are human carbonic anhydrase II and proteinase K (PROK) screened against the Xtal Frag Screen (Jena Bioscience, Germany), with 96 fragments dissolved in DSMO, and endothiapepsin (EP) and Aar/RNaseH (AR) screened against the F2X Entry library (Wollenhaupt et al, 2020), with 96 fragments dissolved in DMSO

Summary

Introduction

Fragments are small organic molecules, often with a molecular weight (MW) of below 200 Da, which can form weak but still specific interactions with proteins. While the low binding affinity of fragments cannot induce a reliable modulation of the activity of their target proteins, their simple structures have the potential to translate into high-efficiency recognition (Carr et al, 2005). This renders fragments a good starting point for the development of ligands with much higher potencies. Because of the substantial impact of structural information on the development of an FBLD-centred hit into a lead compound, XFS can be considered to be one of the most efficient fragmentscreening techniques (Davies & Tickle, 2011; Renaud et al, 2016), despite its relatively low throughput, associated costs and demands on access to large-scale infrastructure, for example electron storage-ring facilities. A good fragment library is designed with follow-up chemistry in mind, and the selected compounds should have good synthetic tractability (Keseru et al, 2016), be accessible and, preferably, have an adequate pool of analogues for structure– activity relationship (SAR) exploration of hit compounds and their cores (Lamoree & Hubbard, 2017)

Platform details

FragMAXlib

User access

FragMAX performance

Findings

Conclusions