Fragment descriptors limitations

An enhancement of the simple substructure approach is the Fragment Reduced to an Environment that is Limited (FREL) method introduced by Dubois et al. [7] With the FREL method several centers of the molecule are described, including their chemical environment. By taking the elements H, C, N, O, and halogens into account and combining all bond types (single, double, triple, aromatic), the authors found descriptors for 43 different FREL centers that can be used to characterize a molecule. 

The adaptations introduced in the fast exchange algorithm to optimize the UCC criterion allow selection from databases of hundreds of thousands of compounds. Currently, the implementation is limited to tens of continuous descriptors, though discrete descriptors like fragment counts could be handled in principle. Further work is also needed for even larger databases with hundreds of descriptors. 

The Minimum Topological Difference (MTD) approach developed by Z. Simon and T. Oprea, especially in its newer MTD-PLS variant employing the PLS regression analysis, successfully relates the activity to the presence and physicochemical parameters of the atoms and fragments defined over a quasi-3D hypermolecule as well as global physicochemical descriptors. Despite some methodological problems and limitations, this approach is promising and in active current development. ... 

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