Searching for Substructures in Fragment Spaces

Abstract

A common task in drug development is the selection of compounds fulfilling specific structural features from a large data pool. While several methods that iteratively search through such data sets exist, their application is limited compared to the infinite character of molecular space. The introduction of the concept of fragment spaces (FSs), which are composed of molecular fragments and their connection rules, made the representation of large combinatorial data sets feasible. At the same time, search algorithms face the problem of structural features spanning over multiple fragments. Due to the combinatorial nature of FSs, an enumeration of all products is impossible. In order to overcome these time and storage issues, we present a method that is able to find substructures in FSs without explicit product enumeration. This is accomplished by splitting substructures into subsubstructures and mapping them onto fragments with respect to fragment connectivity rules. The method has been evaluated on three different drug discovery scenarios considering the exploration of a molecule class, the elaboration of decoration patterns for a molecular core, and the exhaustive query for peptides in FSs. FSs can be searched in seconds, and found products contain novel compounds not present in the PubChem database which may serve as hints for new lead structures.

Shape-Aware Synthon Search (SASS) for Virtual Screening of Synthon-Based Chemical Spaces

“…To navigate such unenumerable libraries, one approach involves using generative models to propose in-library molecules based on learned distributions from a subset of the library. , In another approach, similar to how the libraries are defined by the synthons, virtual screening methods evaluate the synthons instead of the full libraries and only instantiate and evaluate products formed from the best synthons, thereby limiting the computational resources required to evaluate such large chemical spaces. Several two-dimensional (2D) molecular graph-based virtual screening methods that rely on evaluation of synthons have been reported to search ultralarge chemical spaces efficiently. − …”

Fast Substructure Search in Combinatorial Library Spaces

“…The first efficient algorithm to search for substructures in combinatorial libraries was described by Rarey, Volkamer, and Ehrlich. , They propose to first cut the query substructure into all possible subsubstructures, then to match these subsubstructure onto the combinatorial building blocks keeping track of subsubstructure connection points. The hit structures are then constructed from matching building blocks if the subsubstructures reconnection matches the query substructure.…”

Fast Substructure Search in Combinatorial Library Spaces

“…The first efficient algorithm to search for substructures in combinatorial libraries was described by Rarey, Volkamer and Ehrlich. 8,9 Rarey et al propose to first cut the query substructure into all possible sub-substructures, then to match these sub-substructure onto the combinatorial building blocks keeping track of sub-substructure connection points. The hit structures are then constructed from matching building blocks if the sub-substructures reconnection matches the query substructure.…”