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 16,100 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 6,200 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

MW

≤ 300

218

ClogP

< 3

1.07

Fsp³

> 0.45

0.64

TPSA

< 90 Å2

46 Å2

Rotatable bonds

≤ 3

2.1

H-donors

≤ 3

1.2

H-acceptors

≤ 3

2.2

Benzene count

≤ 1

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