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 |
Figure 1. Representative compounds from the Fsp³-enriched Fragment Library
References
- Yang Y. et al. J. Med. Chem. 2010, 53, 7709–7714.
- Ritchie T. J. et al. Drug Discov. Today 2011, 16 (3-4), 164-171.
- Clemons P. A. et al. PNAS 2010, 107 (44), 18787–18792.
- Baell J. B.; Holloway G. A. J. Med. Chem. 2010, 53, 2719–2740.
- Lovering F.; Bikker J.; Humblet C. J. Med. Chem. 2009, 52, 6752–6756.
- Troelsen NS et al. The 3F Library: Fluorinated Fsp3 -Rich Fragments for Expeditious 19 F NMR Based Screening. Angew Chem Int Ed Engl. 2019