Repositioning of quinazolinedione-based compounds on soluble epoxide hydrolase (sEH) through 3D structure-based pharmacophore model-driven investigation.

The development of new bioactive compounds represents one of the main purposes ofthe drug discovery process. Various tools can be employed to identify new drug candidates againstpharmacologically relevant biological targets, and the search for new approaches and methodologiesoften represents a critical issue. In this context, in silico drug repositioning procedures are requiredeven more in order to re-evaluate compounds that already showed poor biological results againsta specific biological target. 3D structure-based pharmacophoric models, usually built for specifictargets to accelerate the identification of new promising compounds, can be employed for drugrepositioning campaigns as well. In this work, an in-house library of 190 synthesized compoundswas re-evaluated using a 3D structure-based pharmacophoric model developed on soluble epoxidehydrolase (sEH). Among the analyzed compounds, a small set of quinazolinedione-based molecules,originally selected from a virtual combinatorial library and showing poor results when preliminarilyinvestigated against heat shock protein 90 (Hsp90), was successfully repositioned against sEH,accounting the related built 3D structure-based pharmacophoric model. The promising resultshere obtained highlight the reliability of this computational workflow for accelerating the drugdiscovery/repositioning processes.