Similarity Searching and Scaffold Hopping in Synthetically Accessible Combinatorial Chemistry Spaces

Abstract

Large collections of combinatorial libraries are an integral element in today's pharmaceutical industry. It is of great interest to perform similarity searches against all virtual compounds that are synthetically accessible by any such library. Here we describe the successful application of a new software tool CoLibri on 358 combinatorial libraries based on validated reaction protocols to create a single chemistry space containing over 10 (12) possible products. Similarity searching with FTrees-FS allows the systematic exploration of this space without the need to enumerate all product structures. The search result is a set of virtual hits which are synthetically accessible by one or more of the existing reaction protocols. Grouping these virtual hits by their synthetic protocols allows the rapid design and synthesis of multiple follow-up libraries. Such library ideas support hit-to-lead design efforts for tasks like follow-up from high-throughput screening hits or scaffold hopping from one hit to another attractive series.

IADE: a system for intelligent automatic design of bioisosteric analogs

“…In principle, any other member of the library is also synthetically accessible. The size of the universe is the product of the numbers of R-groups and can quickly reach infeasible large numbers (scientists at Pfizer estimate that this accessible universe just within Pfizer is 10 12 compounds, based on the Colibri approach [32], which encodes a universe via fragments and linking rules built on known synthetic protocols). It is impractical to explicitly enumerate all these compounds and to search them, so methods have been developed to narrow down the search space, based on representing the molecules as combinations of feature trees.…”

Feature Trees

“…In 2008, Pfizer applied the system to perform similarity searches on 358 combinatorial libraries using the CoLibri (Compound Library Toolkit) system that permits access to more than 10 12 possible final molecules [14]. The system was reported with the specific aim of conducting scaffold hopping campaigns in silico using the Feature Trees representations of the products.…”

SHOP: A Method For Structure‐Based Fragment and Scaffold Hopping

“…[11] Ligand-based approaches use one or more structures of known active compounds as templates; [12] structure-based approaches use the structure of the protein [13] along with various scoring algorithms to select and rank the compounds. In each case, the basic procedure is a three-step process: 1) compound preparation: preparation of the virtual compound library and their descriptors, which can be from different sources (inhouse, commercial, or virtual [14] ); 2) query preparation: prepared from one structure, an ensemble of structures, or a protein; and 3) scoring: using similarity analysis [15] or scoring functions, [16,17] which are then used to rank the compounds in the database. Each variety of VS procedure yields a set of molecules to test, purchase, or synthesize, thus providing various starting points to evaluate.…”