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3D Shape Diverse Fragment Library

1 200 compounds 

Enamine has been working on synthesis of new sp3-rich heterocycles and expanding spirocyclic chemistry already over 16 years. Our own research in this area enabled synthesis of large variety of 3D shaped molecules that are well represented in stock Screening Collection. Design and synthesis of aliphatic conformationally restricted core molecules (often exclusive only to Enamine) followed by parallel chemistry modification led to a number of readily available analogs; that is a crucial point in fragment hit optimization and follow-up.

By applying common criteria used in design of 3D fragment libraries to Enamine Stock Collection, we created a set of 3D-shaped diverse fragments, which provides optimal representation of available molecular shape diversity with a small compound collection.

Examples of the compounds included into 3D-Shaped Diverse Fragment Library

More information

The following criteria and algorithms have been applied to the library design:

  • Ro3 compliant fragment set was refined with strict structural filters and Fsp3 cut-off at 0.35
  • Three-dimensionality criteria were applied: nPMI1 ≥ 0.15; nPMI2 ≥ (1.15 – nPMI1) (see PMI plot 1)
  • K-mean clustering of preselected 8 000 3D fragments was performed using nPMI1 and nPMI2 values. Only 1 200 centroid molecules were included in the final set (see PMI plot 2)
Parameter Range
MW 120 … 300
Heavy atoms 8 … 19
ClogP -1.5 … 3
HBD 0 … 3
HBA 0 … 3
RotBonds 0 … 3
TPSA, Å2 ≤ 80
Aromatic rings ≤ 2
N+O count 1 … 9
Chiral centers ≤ 2
S count ≤ 1
Cl, Br, CN, amide, synfonamide counts ≤ 1

PCA  analysis plot

PCA analysis plot showing distribution of the library members (descriptors used for analysis: nPMI1, nPMI2, PSA, HBA, HAC, mRDF70)

: green dots correspond to 8 000 compounds indicated as 3D Fragments Set from Enamine in-stock Ro3 compliant molecules (grey dots) distribution of molecules in the library (centroids, blue spots) among of 8 000 of 3D-shaped initial set
PMI plot 1: 8 000 3D Fragments (green dots) compared to other Enamine in-stock Ro3 compliant molecules (grey dots)

PMI plot 2: Final 3D-Shaped Diverse Fragment Library (blue dots) compared to other 3D Fragments (grey dots)

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