Exhaustive sampling of the fragment space associated to a molecule leading to the generation of conserved fragments

Abstract

The first step in hit optimization is the identification of the pharmacophore, which is normally achieved by deconstruction of the hit molecule to generate "deletion analogues." In silico fragmentation approaches often focus on the generation of small fragments that do not describe properly the fragment space associated to the deletion analogues. We present significant modifications to the molecular fragmentation programme molBLOCKS, which allows the exhaustive sampling of the fragment space associated with a molecule to generate all possible molecular fragments. This generates larger fragments, by combining the smallest fragments. Additionally, it has been modified to deal with the problem of changing pharmacophoric properties through fragmentation, by highlighting bond cuts. The modified molBLOCKS programme was used on a set of drug compounds, where it generated more unique fragments than standard fragmentation approaches by increasing the number of fragments derived per compound. This fragment set was found to be more diverse than those generated by standard fragmentation programmes and was relevant to drug discovery as it contains the key fragments representing the pharmacophoric elements associated with ligand recognition. The use of dummy atoms to highlight bond cuts further increases the information content of fragments by visualizing their previous bonding pattern.

Keywords: algorithm development; chemical space analysis; fragment based drug discovery; molecular fragmentation.