Abstract
Over the last two decades, fragment-based drug discovery (FBDD) has emerged as an effective and efficient method to identify new chemical scaffolds for the development of lead compounds. X-ray crystallography can be used in FBDD as a tool to validate and develop fragments identified as binders by other methods. However, it is also often used with great success as a primary screening technique. In recent years, technological advances at macromolecular crystallography beamlines in terms of instrumentation, beam intensity and robotics have enabled the development of dedicated platforms at synchrotron sources for FBDD using X-ray crystallography. Here, the development of the Fast Fragment and Compound Screening (FFCS) platform, an integrated next-generation pipeline for crystal soaking, handling and data collection which allows crystallography-based screening of protein crystals against hundreds of fragments and compounds, at the Swiss Light Source is reported.
Highlights
The identification of small molecules that modulate protein function and activity is a crucial step in drug development
The Swiss Light Source (SLS) macromolecular crystallography (MX) group has recently developed their own X-ray crystallographic FBDD (xFBDD) platform, called the Fast Fragment and Compound Screening (FFCS) platform. We present this newly established FFCS pipeline, focusing on hardware and software solutions
Whereas the hardware setup for the FFCS pipeline is based on existing XChem solutions, the FFCS software suite was developed in-house
Summary
The identification of small molecules that modulate protein function and activity is a crucial step in drug development. FBDD is an alternative to high-throughput screening (HTS), which uses biochemical or biophysical assays to search for lead compounds within large libraries that have tens of thousands to millions of members (Fox et al, 2006). The size of these libraries presents significant logistical challenges, but they can still sample only a small portion of the possible combinatorial chemical space (Hann & Oprea, 2004) and are frequently expanded to address new targets. In addition to its use in validating and characterizing the binding of fragment hits identified by other techniques, X-ray crystallography has achieved great success as a primary screening method. We present this newly established FFCS pipeline, focusing on hardware and software solutions
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