Fragments
3D-rich Fragment Libraries
Library Design
LCC have designed a 3D-rich fragment library based on nine sp3-rich heterocyclic cores:
The library consists of 43,226 unique compounds that are chemically tractable using LCC’s synthetic methods.
Library Properties
| MW |
Solubility (mM) |
AlogP |
#H Bond Donors |
#H Bond Acceptors |
|
| Average |
234.43 |
148.19 |
1.03 |
0.99 |
3.12 |
| SD |
50.7 |
431.0 |
1.5 |
0.8 |
3.0 |
Rule of 3 library
Library Design
- Sublibrary of Building block/scaffold library
- No protecting groups
- No esters
- Acceptable aqueous solubility
- Rule of 3 compliant
- No PAINS, Rishton fragments, “Bad groups” etc.
Baell, J. et al. J Med Chem, 2010, 53(7), 2719
Rishton, G. M. DDT, 1997, 2(9), 382
Hann, M. J. Chem. Inf. Comput. Sci., 1999, 5, 897
Muegge, I. Med. Res. Rev., 2003, 23(3), 302
Final set of criteria:
- Calculated aqueous solubility > 1 milliM
- AlogP ≤ 3
- Molecular weight ≤ 300
- #H bond donors ≤ 3
- #H bond acceptors ≤ 3
- PSA ≤ 60 Å2
- #Rotable bonds ≤ 3
| MW |
Solubility (mM) |
AlogP |
#H Bond Donors |
#H Bond Acceptors |
|
| Average |
192.18 | 144.08 |
0.94 |
0.83 | 2.52 |
| SD |
33.2 |
380.0 |
1.0 | 0.7 | 0.6 |
CNS Library
LCC’s synthetic technologies allow the production of novel, heterocyclic based small molecules. Our patented technology provides access to chiral piperidines.Upon analysis of the FDA approved drugs, we noticed that piperidines are the most frequently occurring heterocycle. In addition, piperidines are also the most prevalent heterocycle in clinically approved CNS (Central Nervous System) compounds.
Therefore, we set out to apply our technology to the synthesis of a focussed library targeted at the CNS.
Examination of the physicochemical/Lipinski space of LCC compounds cf CNS approved drugs there is a high degree of similarity, i.e. low MW (<400), low logP (<5), #H bond donors (95% library <5), #H bond acceptors (<8)
LCC produced an initial library set of ~112k molecules, which was designed in partnership with Medchemica, using MMPA and their grand rule database. The library was also designed in order to ensure a good range of functionality was incorporated.
We then decided on the criteria upon which to optimise the library:
Physicochemical and CNS penetration criteria were selected based on published literature (e.g. Ro3), experience (solubility > 1 miliM) and targeting the CNS (MPO >4).
- MPO score devised by Pfizer:
- CNS penetration required
- Guidelines suggested - different to Lipinski’s
- MPO score - probability of CNS penetration
- 74% CNS drugs have MPO score > 4
- 6 key physicochemical parameters (logP, logD, TPSA, MW, HBD, HBA, pKa) drive library design
Final set of criteria:
- Calculated aqueous solubility > 1 milliM
- MPO score ≥ 4
- AlogP ≤ 3
- Molecular weight ≤ 300
- #H bond donors ≤ 3
- #H bond acceptors ≤ 3
- PSA ≤ 60 Å2
- #Rotable bonds ≤ 3
Library Properties
Results: Out of the initial set of 43226 compounds, 12630 (29%) successfully met all of the criteria.
| MW |
Solubility (mM) |
AlogP |
#H Bond Donors |
#H Bond Acceptors |
MPO |
|
| Average |
193.93 | 147.67 |
0.92 |
0.85 | 2.57 |
5.05 |
| SD |
33.2 |
387.3 |
1.0 | 0.7 | 0.6 |
0.5 |
A library of ~13k small, fragment like, highly soluble, CNS penetrant compounds has been designed.