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.

LibINVENT: Reaction-based Generative Scaffold Decoration for in Silico Library Design

“…Recently, exhaustive slicing of single-bonds according to RECAP 23 rules has been explored 17,18 . While this approach appears natural at a glance, it is not always effective for a wet lab chemist attempting to synthesise the proposed compounds 24 . The ability to follow real chemical reactions when decorating the scaffold is crucial; our experiments demonstrate that training on data sliced according to RECAP rules does not teach the prior to understand these chemical principles.…”

“…There are many ways of slicing a molecule to obtain scaffold–decoration pairs for training a decorator model . Recently, the exhaustive slicing of single bonds according to RECAP rules has been explored. , Whereas this approach appears natural at a glance, it is not always effective for a wet lab chemist attempting to synthesize the proposed compounds . Whereas the default RECAP rules, which include 11 bond cleavage types (amide, amine, ester, urea, ether, olefin, quaternary nitrogen, aliphatic carbon with aromatic nitrogen, lactam nitrogen with aliphatic carbon, aromatic carbon with aromatic carbon, and sulphonamide), aim to slice the molecules and identify preferred structural motifs, they still leave some cleaving possibilities out.…”

“…16,17 Whereas this approach appears natural at a glance, it is not always effective for a wet lab chemist attempting to synthesize the proposed compounds. 22 Whereas the default RECAP rules, which include 11 bond cleavage types (amide, amine, ester, urea, ether, olefin, quaternary nitrogen, aliphatic carbon with aromatic nitrogen, lactam nitrogen with aliphatic carbon, aromatic carbon with aromatic carbon, and sulphonamide), aim to slice the molecules and identify preferred structural motifs, they still leave some cleaving possibilities out. The ability to follow real chemical reactions when decorating the scaffold is crucial; our experiments demonstrate that training on data sliced according to RECAP rules does not teach the prior to understand these chemical principles.…”

Lib-INVENT: Reaction Based Generative Scaffold Decoration for in silico Library Design

“…Recently, exhaustive slicing of single-bonds according to RECAP 21 rules has been explored 16,17 . While this approach appears natural at a glance, it is not always effective for a wet lab chemist attempting to synthesize the proposed compounds 22 . While the default RECAP rules, which include 11 bond cleavage types (amide, amine, ester, urea, ether, olefin, quaternary nitrogen, aliphatic carbon with aromatic nitrogen, lactam nitrogen with aliphatic carbon, aromatic carbon with aromatic carbon and sulphonamide), are aiming to slice the molecules and identify preferred structural motifs they still leave some cleaving possibilities out.…”

Towards systematic exploration of chemical space: building the fragment library module in molecular property diagnostic suite

“…However, BRICS rules are the expansion of the RECAP rules that consider the environment of every bond type and its surrounding substructures [ 13 , 14 ]. In addition, some other fragmentation methods and unexplored fragments spaces are need to be explored [ 15 – 17 ]. Consequently, many fragmentation techniques for FBDD have been developed which consider binding site and fragment connection information from a macromolecule-ligand complex [ 18 – 25 ].…”