Platforms and Services

Fragment-Based Drug Discovery (FBDD) is a way to rapidly develop early lead compounds. FBDD has been used to develop over 40 clinical candidates and several FDA-approved drugs.

FBDD enables scientists to rapidly:

1. sample a large chemical space using a small library,
2. develop lead compounds with novel intellectual property
3. identify critical binding motifs and uncover allosteric sites.

Furthermore, because fragment hits have a low molecular weight, they leave chemical space to optimize potency, selectivity and DMPK properties. In practice, it is often easier to generate a drug-like lead compound from fragment hits than it is to modify drug-like properties into an initially promising HTS hit.

In FBDD, a target protein is screened against a fragment library of 500-1000 low molecular weight compounds (100-300 Daltons). FBDD contrasts with traditional High Throughput Screening (HTS) methods which tend to utilize very large chemical libraries, sometimes containing millions of complex compounds. While HTS compounds may initially have impressive affinity through an accumulation of sub-optimal interactions, they can be difficult to optimize. Fragment binding relies on a small number of finely-tuned efficient atomic interactions. Fragments are often characterized by the metric “Ligand Efficiency” (LE), which can be thought of as using a minimal number of atoms to achieve binding. Fragment hits tend to have high LE because the experimental design selects low molecular weight compounds that can bind within the detection limits.

	HTS	FBDD
Library	106	103
M.W.(Da.)	500-1000	100-300
Hit Rate	<<<1%	3-5%
Initial Hits	nM - μM	μM - mM

FBDD can be approached using structural (crystallography, NMR), biophysical (assays, SPR) or even in silico screening. Structure-based fragment screening using x-ray crystallography is a robust and sensitive label-free way to clearly identify hits. Fragment concentration is key to screening success. Protein crystals can be soaked in high fragment concentrations (1-10 mM), suitable for detecting weak binders. Biochemical and cell-based assays run at high concentrations risk introducing false positives, non-specific binding, and ambiguous data. On the other hand, you may miss valuable hits by running biochemical assays with fragment concentrations that are too low. In some cases, an initial biochemical pre-screen is used before it is validated using crystallography.

Crystal structures provide clear and specific fragment binding orientation, making the hits ready for elaboration with medicinal chemistry, “SAR by catalog”, scaffold hopping, linking, and growing.

1. Select fragments, optimize protein crystals
2. Soak protein crystals in fragment mixtures
3. High-throughput structure determination
4. Fragment Hit-to-Lead Design 1

Our streamlined high-throughput crystallography will get the fragment hits you need fast. A crystallographic screen of 500-1000 fragments can be done using approximately 100 crystals soaked in shape-diverse mixtures. Hit rates typically range from 3-5%, thus screening a 500-compound fragment library could be expected to yield 15-25 fragment-bound protein crystal structures. Our scientists have practical hands-on experience to deliver FBDD results for you.