Fragment Diversity Subsets with Experimental Solubility

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 two novel Soluble Fragment Diversity Subsets of 960 (Subset 1) and 320 (Subset 2) drug-like fragments to provide an efficient starting kit for FBDD research projects.

Key features:

  • 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

The average physicochemical values and their relative distribution are reported in Table 1, Figures 1-2 below.

The pre-selected subsets are provided as solids in 96-well plates. Please, request other formatting options at orders@lifechemicals.com. We will be happy to provide these fragment subsets in the format most convenient for your project needs (DMSO solutions of different volume/concentration, 96-/384-well plates, etc.).

 

Parameter

 

Range

Average Values

Subset 1

Subset 2

Number of compounds

 

960

320

MW

100 – 300

211.77

195.98

ClogP

-2 - 3

1.34

1.13

TPSA

10 – 135

51.43

55.37

Rotatable bonds

0 – 3

1.94

1.70

H-donors

0 – 3

1.27

1.18

H-acceptors

0 – 3

2.28

2.33

Ring count

0 – 5

2.13

1.89

СLogS

-5 – 2

-2.17

-2.09

Diversity

>45%

47%

62%

Table 1. Range and average values of main physicochemical properties in 2 screening compound subsets

 

Physicochemical value distributions of the Fragment Screening Subset 1 (960 compounds)

Figure 1. Physicochemical value distributions of the Fragment Screening Subset 1 (960 compounds)

 

Physicochemical value distributions of the Fragment Screening Subset 2 (320 compounds)

Figure 2. Physicochemical value distributions of the Fragment Screening Subset 2 (320 compounds)

 

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.