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 7,100 small-molecule compounds were selected for the Library.
Additionally, an advanced subset of over 3,400 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 |
183 |
189 |
|
ClogP |
-3 - 3 |
0.9 |
1.0 |
|
TPSA |
0 - 100 Å2 |
51 Å2 |
45 Å2 |
|
Rotatable bonds |
≤ 2 |
1.4 |
1.5 |
|
H-donors |
≤ 3 |
1.3 |
1.3 |
|
H-acceptors |
≤ 6 |
2.4 |
2.2 |
|
Ring count |
1 - 3 |
1.9 |
2.0 |
Cherry-picking is available. Please, contact us at orders@lifechemicals.com for any details and quotations.
Figure 1. Representative compounds from Low MW Fragment Library
References
- Wenlock M. C. et al. J. Med. Chem. 2003, 46, 1250–1256.
- Hann M. M. Part of the Series: NATO Science for Peace and Security, Series A: Chemistry and Biology. 2015, 183–196.
- Bruns R. F.; Watson I. A. J. Med. Chem. 2012, 55, 9763–9772.
- Baell J. B.; Holloway G. A. J. Med. Chem. 2010, 53, 2719–2740.
- Thien TV et al. Dokl Biochem Biophys. 2017 Sep;476(1):316-319.
- Chen Y et al. Chemosphere. 2018 May;198:226-237.
- Lazzarino G et al. Hum Reprod. 2018 Oct 1;33(10):1817-1828.
- O'Reilly M. Drug Discov Today. 2019 May;24(5):1081-1086.