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Fsp³-enriched Screening Compound Library

Molecular complexity and presence of chiral centers were proven to increase the chances of organic compounds to become suitable drug candidates. This finding has resulted in high demand for advanced molecular structures based on sp3-hybridized carbons.

In response to these market needs, Life Chemicals has designed its Fsp3-enriched Screening Compound Library, having carefully selected over 63,700 sp3-richnon-flat screening compounds from its proprietary HTS Compound Collection. These novel drug-like molecules possess an increased Fsp3 fraction ≥ 0.47 (mean value 0.57), as well as high chemical and structural diversity. The compound distribution for individual physicochemical parameters is illustrated in Figure 1. Many structures contain spiro, bridged and fused rings and stereogenic centers to cover more advantageous chemical space.

This original Screening Set can significantly facilitate HTS efforts to discover novel ligands for challenging drug targets.

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 Focused Libraries.

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Background

In the 2000s, a new “Escape from Flatland” concept was introduced. It was shown that the mean Fsp3 (saturation degree Fsp3 = number of sp3 hybridized carbons / total carbon count) increases from 0.36 for 2.2 million molecules at the development stage to 0.47 for 1,179 approved drugs [1-11]. Combined with low molecular weight and ClogP values, a higher Fsp3 count leads to higher bioavailability and specificity of compounds, thus making them attractive for the drug discovery process.

In comparison to mostly flat aromatic compounds, sp3-enriched scaffolds possessing a greater saturation level display improved physicochemical properties (higher solubility and lower melting points - factors likely to improve oral bioavailability), as well as a general tendency towards higher target selectivity, resulting from fewer unspecific interactions.

Compound selection

To create this Screening Library of drug-like sp3-enriched molecules, we applied Fsp3 cut-off at > 0.47 and specific physicochemical parameters, derived as a result of a combined analysis of publications on this subject [1–11], to filter the HTS Compound Collection (Table 1). The PAINS filter together with our in-house developed toxicophore and undesired functionalities filters were also applied. Simple reagents and trivial chemotypes were excluded from the resulting Screening Set to deliver over 63,700 drug-like sp3-rich screening compounds.

Compound distribution by the key parameters in the Fsp3-enriched Screening Compound Library.

Figure 1. Compound distribution by the key parameters in the Fsp3-enriched Screening Compound Library.

Table 1. Physicochemical parameters used for screening compound selection

Parameter MW Fsp3 ClogP TPSA, Å2 RotB HBD HBA Number of carbonaromatics
Selection range 175 – 450 ≥ 0.47 < 4 < 140 ≤ 8 ≤ 4 ≤ 8 ≤ 1
Average value 327 0.57 1.6 74 4.6 1.4 3.7 0.44

 

Representative non-flat small molecule screening compounds

References

  1. AstraZeneca J. Med. Chem. 2010, 53, 7709–7714.
  2. GSK, Drug Discov. Today, 2011, 16, 3/4.
  3. Broad Institute of Harvard and MIT, PNAS 2010, 107, 44, 1878718792.
  4. The Walter and Eliza Hall Institute of Medical Research, J. Med. Chem. 2010, 53, 2719–2740.
  5. Wyeth, J. Med. Chem. 2009, 52, 6752–6756.
  6. Yang Y. et al. J. Med. Chem. 2010, 53, 7709-7714.
  7. Ritchie T. J. et al. Drug Discov. Today 2011, 16 (3-4), 164-171.
  8. Clemons P. A. et al. PNAS 2010, 107 (44), 18787-18792.
  9. Baell J. B.; Holloway G. A. J. Med. Chem. 2010, 53, 2719-2740.
  10. Lovering F.; Bikker J.; Humblet C. J. Med. Chem. 2009, 52, 6752-6756.
  11. Troelsen NS et al. Angew Chem Int Ed Engl. 2019
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