Fragment-based drug design (FBDD) has emerged as an efficient and productive route for de novo drug discovery
Reviewed by Susan Boyd, CompChem Solutions, Cambridge, UK
Within the space of only a few years, fragment-based drug design (FBDD) has emerged as an efficient and productive route for de novo drug discovery. However, software specifically designed to support the approach has only recently come to the fore, and BioSolveIT are at the leading edge of the field, with their armoury of FlexNovo, FlexXc, Recore and FTrees-FS.
It could be argued that the de novo ligand design tools of the 1980s are the ancestors of the FBDD methods employed today, as many of these employed fragment-placement and linking methods to design the new structures. FlexNovo has built on this concept, but brings the technology right up to date, building a degree of chemical intelligence into the designed structures, and employing the widely respected FlexX scoring algorithm to rank the derived structures.
FlexXc is an add-on module to the FlexX docking software designed for efficient docking of combinatorial libraries into a protein target, whereby core fragment placements are re-used and combined with various R-groups as per a given combinatorial library protocol. As such, the tool can be used to prioritise within a series of core fragments of interest, or to identify suitable R-group fragments to attach to a given core.
FTrees, on the other hand, are fuzzy, topology-based descriptors akin to a 2D feature-based pharmacophore approach. Using these in conjunction with the FTrees-FS software, fragment spaces can be searched to identify both complete, de novo structures, or simply fragments which are similar to the query.
Again from the ligand-based perspective, Recore is another ligand-based tool designed to identify alternative core fragments which can replace a given core, connecting the fixed terminal portions of a query molecule. Pharmacophore information can additionally be applied to guide the output.
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