Discovery of a nanomolar glyoxalase-I inhibitor using integrated ligand-based pharmacophore modeling and molecular docking

In this study we were aiming to identify potent GLO-I inhibitors as potential candidates for the development of effective anticancer therapeutics using an integrated ligand- and structure-based drug design approach. A set of selective pharmacophore models was generated using an in-house tested set of flavonoids and used in virtual screening of Maybridge and Aldrich databases, collectively containing more than 64,000 compounds. Filtration of retained hits resulted in 362 compounds that were docked into the active site of the GLO-I enzyme. Then, the top 30% of docked compounds were visually inspected and 32 compounds were purchased and biologically evaluated. Five compounds showed good to excellent inhibitory activities with the most active one (compound14, ID number ST018515) showing an IC50 of 336  nM. A high hit rate of actives implies the success of our approach. The five active compounds with considerable structural diversity were identified as novel leads that can be further optimized towards designing potent GLO-I inhibitors.
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research