SpaceHASTEN: A Structure-Based Virtual Screening Tool for Nonenumerated Virtual Chemical Libraries

Given the size of the relevant chemical space for drug
discovery,
working with fully enumerated compound libraries (especially in three-dimensional
(3D)) is unfeasible. Nonenumerated virtual chemical spaces are a practical
solution to this issue, where compounds are described as building
blocks which are then connected by rules. One concrete example of
such is the BioSolveIT chemical spaces file format (.space). Tools
to search these space-files exist that are using ligand-based methods
including two-dimensional (2D) fingerprint similarity, substructure
matching, and fuzzier similarity metrics such as FTrees. However,
there is no software available that enables the screening of these
nonenumerated spaces using protein structure as the input query. Here,
a hybrid ligand/structure-based virtual screening tool, called SpaceHASTEN,
was developed on top of SpaceLight, FTrees, LigPrep, and Glide to
allow efficient structure-based virtual screening of nonenumerated
chemical spaces. SpaceHASTEN was validated using three public targets
picked from the DUD-E data set. It was able to retrieve a large number
of diverse and novel high-scoring compounds (virtual hits) from nonenumerated
chemical spaces of billions of molecules, after docking a few million
compounds. The software can be freely used and is available from http://github.com/TuomoKalliokoski/SpaceHASTEN.