Fragment-based Screening (FBS)

Fragment-based screening (FBS) is a widely utilized strategy for the discovery of lead compounds. Especially in the development of drugs against unconventional targets such as protein-protein interactions (PPIs), FBS has proven to be a viable alternative to high-throughput screening (HTS). Leveraging advanced fragment-based drug design (FBDD) platform, Creative Biostructure provides FBS solutions for customers with hit identification needs, which involve various biophysical methods to determine the exact binding fragments.

Fragment-based Screening (FBS)Figure 1. Comparison of HTS and fragment-based screening.

Compared with HTS, fragment-based screening has the following features:

 FBSHTS
Library CapacityLibrary typically <5,000Library typically >100,000
Molecular WeightMolecular weight <300DaMolecular weight >300Da
CoverageA much greater chemical space can be efficiently probedCoverage of chemical space can be poor
Target SpecificityWell-characterized targetsA broader range of targets including whole-well screening approaches
AbilityIterative step-by-step optimization possible to increase the size and potency of the moleculeCan be difficult to optimize hits as the structures can be complex
ThroughputLow-medium throughputHigh throughput

Therefore, FBS enables a larger chemical structure space to be more effectively probed with fewer compounds and hit rates for FBS appear to be higher (3-10%). At Creative Biostructure, we support the use of many biophysical techniques to measure the weak and medium affinity of fragments. These biophysical techniques can provide insight into the binding mode of fragments, allowing fragment hits to be developed into lead-like compounds in a structure-guided approach. We recommend using two different screening techniques and then focusing on the fragments that are active in both assays.

Our screening methodologies includes but is not limited to:

Capabilities and advantages of our Fragment-based Screening services:

  • We have the ability to provide one-stop FBDD solutions, including but not limited to, target selection, target protein production, fragment library design, screening, validation of hits and development of the fragments into a lead compound.
  • We can utilize computational technology (i.e. virtual fragment screening) to find potentially active fragments and predict the binding mode, so as to conduct a screening for the next step with other more accurate experimental methods.
  • The fragment library for screening can be provided by Creative Biostructure or by customers, and our fragment library capacity is greater than 2000 small molecules, which is composed of internally synthesized fragments, commercial chemical library fragments, pharmacophore fragments designed according to FDA-approved drugs, etc.
  • We can provide target protein production services, and we have a number of ready-made hot target proteins and crystal structures.
  • Each of the FBS biophysical methods we provide is sensitive enough to detect hits with Kd values in the mM to the high μM range.

Creative Biostructure is committed to providing customers with cost-effective, high-quality solutions for hit identification. Our team has a deep understanding of FBS-related biophysical screening techniques and can propose appropriate experimental protocols according to the specific projects of customers, professionally explain the screening results, and assist in downstream optimization.

References

  1. Murray C W, Rees D C. The rise of fragment-based drug discovery. Nature chemistry. 2009, 1(3): 187-192.
  2. Robson-Tull J. Biophysical screening in fragment-based drug design: a brief overview. Bioscience Horizons: The International Journal of Student Research. 2018, 11.
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