Diversity Screening Subsets of Soluble Fragments

Fragment-based drug discovery (FBDD) is an efficient and affordable approach in drug discovery research for the majority of common protein targets, for instance, kinases or proteases. There has also been growing success on more challenging tasks such as disruption of protein-protein interactions. The key feature of the FBDD approach is starting discovery with the identification of low molecular weight compounds or fragments that bind to the biological molecule of interest. They are small and less likely to contain moieties that prevent binding, and as such, they are more likely to identify functional motifs that match the requirements of the selective target.

Given that fragments typically bind weakly to a  target protein, measurement of binding interaction is conducted at a higher concentration, which requires a better solubility of fragments to avoid producing false results. Therefore, the design of a high-quality fragment screening library, using thorough structure-based and chemoinformatics analyses together with experimental solubility assessment is of top priority.

Life Chemicals has designed novel diversity-orientated screening sets of fragment-like compounds with experimental solubility data to provide an efficient starting kit for FBDD research projects.

Key features:

• Optimized size: screening pools of 1,280, 960 and 320 drug-like low molecular weight fragments
• High structure diversity: average Tanimoto index < 0.53 (Diversity >47 %)
• Experimentally assured solubility at 200mM in the DMSO solution
• Drug-like physicochemical properties: the Rule of Three compliant
• Optimal molecular complexity
• No PAINS, REOS or toxicophore/undesired functionalities: filtered by previously reported and in-house developed medicinal chemistry filters
• Various formatting options available
• Provided as solids in 96-well plates or pre-plated DMSO solutions

The compound selection can be customized based on your requirements, cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

For a pre plated set based on this Screening Library, please explore our Pre-plated Fragment Screening Sets.

We will be happy to provide these structurally-diverse fragment subsets in the format most convenient for your project needs (DMSO solutions of different volume/concentration, 96-/384-well plates, etc.).

The average physicochemical values and their relative distribution are reported in Table 1, Figures 1-3 below.

Table 1. Range and average values of main physicochemical properties in 3 structurally-diverse fragment screening compound subsets 

Figure 1. Physicochemical value distributions of the Fragment Screening Set 1 (1,280 compounds)
 

Figure 2. Physicochemical value distributions of the Fragment Screening Set 2 (960 compounds)

Figure 3. Physicochemical value distributions of the Fragment Screening Set 3 (320 compounds) 

Representative Fragments with Experimental Solubility Data

F6608-3057

F6543-1209

F6543-8986

F6438-6405

F6608-0432

F8889-8913

F6543-0286

F6657-1527

F6614-2465

F1905-9009

F9994-0420

F2167-1314

F6616-3148

F6608-1264

F6481-2376

F6617-2013

F6616-6637

F6660-2928

References:

1. Chen H, Zhou X, Wang A, Zheng Y, Gao Y, Zhou J. Evolutions in fragment-based drug design: the deconstruction-reconstruction approach // Drug Discov Today. 2015, 20(1):105-13.
2. Shi Y, von Itzstein M. How Size Matters: Diversity for Fragment Library Design // Molecules. 2019 Aug 5;24(15). pii: E2838. doi: 10.3390/molecules24152838.
3. Erlanson DA, Fesik SW, Hubbard RE,4, Jahnke W, Jhoti H. Twenty years on: the impact of fragments on drug discovery // Nat Rev Drug Discov. 2016 Sep;15(9):605-619.
4. Osborne J, Panova S, Rapti M, Urushima T, Jhoti H. Fragments: where are we now? // Biochem Soc Trans. 2020 Feb 28;48(1):271-280.
5. Lamoree B, Hubbard RE. Current perspectives in fragment-based lead discovery (FBLD) // Essays Biochem. 2017 Nov 8;61(5):453-464.