Low MW Fragment Library

Many vendors are offering libraries for FBDD, mainly being guided by the well-known Rule of Three in their design. However, in most of these libraries, the physicochemical parameters of the compounds tend to be closer to their upper limits (MW = 300, ClogP = 3).

Notably, recent tendencies in drug discovery shift towards aiming at leads with lower molecular weight and higher hydrophilicity. It is not surprising, therefore, that even more meticulous criteria must be applied to fragment libraries. In particular, lowering the upper molecular weight cut-off value (200 – 240 instead of 300) is strived for by many companies employing the FBDD approach and HTS campaigns in their research.

To meet these principles, Life Chemicals has designed its Low MW Fragment Library applying several physicochemical filters [1, 2] to its General Fragment Collection. Although the molecular weight is the main parameter which was controlled strictly, other physicochemical characteristics were also well monitored (e. g., more than 80 % of the Library has ClogP < 2). Finally, the compounds were passed through MedChem [3] and PAINS [4] structural filters. Over 6,300 small-molecule compounds were selected for the Library.

Additionally, an advanced subset of over 4,900 drug-like fragments was generated employing more rigorous structural filters. 

 

Parameter

 

Range

Average Values

Low MW Fragment Library

Advanced Low MW Fragment Subset

MW

100 - 225

184

185

ClogP

-3 - 3

0.9

0.9

TPSA

0 - 100 Å2

50 Å2

48 Å2

Rotatable bonds

≤ 2

1.4

1.4

H-donors

≤ 3

1.3

1.3

H-acceptors

≤ 6

2.3

2.3

Ring count

1 - 3

1.9

1.9

  Representative fragments with low molecular weight

Figure 1. Representative compounds from Low MW Fragment Library

References

  1. Wenlock M. C. et al. J. Med. Chem. 2003, 46, 1250–1256.
  2. Hann M. M. Part of the Series: NATO Science for Peace and Security, Series A: Chemistry and Biology. 2015, 183–196.
  3. Bruns R. F.; Watson I. A. J. Med. Chem. 2012, 55, 9763–9772.
  4. Baell J. B.; Holloway G. A. J. Med. Chem. 2010, 53, 2719–2740.
  5. Thien TV et al. Dokl Biochem Biophys. 2017 Sep;476(1):316-319.
  6. Chen Y et al. Chemosphere. 2018 May;198:226-237.
  7. Lazzarino G et al. Hum Reprod. 2018 Oct 1;33(10):1817-1828.
  8. O'Reilly M. Drug Discov Today. 2019 May;24(5):1081-1086.