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

Abstract

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.