Fsp³-enriched Fragment Library

In response to new trends in drug discovery, involving comprehensive structural analysis of approved drugs and determination of relationships between molecular complexity and pharmacological promiscuity of drug-like compounds [1–5], Life Chemicals has extrapolated the results of investigations described here to its Fragment Library design.

Recently it was found that the mean saturation degree Fsp³ value goes up from 0.36 for 2.2 million molecules in the drug discovery phase to 0.47 for 1,179 approved drugs. Applying the Fsp³ cut-off at 0.45 to the Life Chemicals General Fragment Library resulted in our Fsp³-enriched Fragment Library of around 17,800 compounds.

Superposition of sets of the compounds with a relatively high Fsp³ value and filtering them by strict Rule of Three criteria along with TPSA 90 Å2 cut-off gives rise to our Advanced Fsp³-enriched Fragment Subset comprising more than 8,500 sp³-rich compounds. To ensure discarding “ugly” compounds, PAINS and our in-house developed toxicophore and undesired functionalities filtering were applied as well.

Physicochemical parameters of the Advanced Fsp³-enriched Fragment Library Subset are summarized in the table below:

 


Parameter

Range
Average Values
General   Subset
MW ≤ 300 247 223
ClogP < 3 1.03 1.00
Fsp³ > 0.45 0.62 0.64
TPSA < 90 Å2 60 Å2 49 Å2
Rotatable bonds ≤ 3 3.4 2.1
H-donors ≤ 3 1.3 1.2
H-acceptors ≤ 3 2.9 2.4
Benzene count ≤ 1 0.7 0.5

 

Representative Fsp³-enriched fragments

Figure 1. Representative compounds from the Fsp³-enriched Fragment Library

 References

  1. Yang Y. et al. J. Med. Chem. 2010, 53, 7709–7714.
  2. Ritchie T. J. et al. Drug Discov. Today 2011, 16 (3-4), 164-171.
  3. Clemons P. A. et al. PNAS 2010, 107 (44), 18787–18792.
  4. Baell J. B.; Holloway G. A. J. Med. Chem. 2010, 53, 2719–2740.
  5. Lovering F.;  Bikker J.; Humblet C. J.  Med. Chem. 2009,  52,  6752–6756.
  6. Troelsen NS et al. The 3F Library: Fluorinated Fsp3 -Rich Fragments for Expeditious 19 F NMR Based Screening. Angew Chem Int Ed Engl. 2019
This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used. By using our website, you accept our conditions of use of cookies to track data and create content (including advertising) based on your interest. Accept