Abstract
Background: Pharmacophore modeling has become an integrated tool in drug discovery. However, no prospective study compares the performance of the available software. Methods: The two widely used pharmacophore modeling and screening software programs Discovery Studio and LigandScout were used to generate, validate, and prospectively apply COX-1 and -2 models. Selected virtual hits were tested in cell-free enzymatic assays. The correct retrieval of active compounds was compared. Results: In the enzymatic testing, 10.5% of the tested hits for COX-2 and 6.6% of the predicted compounds for COX-1 were active. To directly compare the two models, both based on the same PDB entry, were selected for virtual screening. The two programs yielded vastly different hit lists, but both predicted active compounds. Conclusion: To obtain a comprehensive selection of active compounds, more than one program should be used for modeling.
Financial & competing interests disclosure
The authors thank the Austrian Science Fund (FWF) National Research Network (NFN) Project “Drugs from nature targeting inflammation” (S10711), Austrian Exchange Service (ÖAD-WTZ project CZ14/2013), the Czech Ministry of Education, Youth and Sports project 7AMB13AT008, the foundation “Verein zur Förderung der wissenschaftlichen Ausbildung und Tätigkeit von Südtirolern an der Landesuniversität Innsbruck”, and the Erika Cremer Habilitation Program of the University of Innsbruck for financial support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.