Pharmacophore-based discovery of new human dihydroorotate dehydrogenase inhibitor

Pharmacophore models of human dihydroorotate dehydrogenase (HsDHODH) have been developed using Discovery Studio V2.1 with a training set of 27 HsDHODH inhibitors. With one hydrogen bond receptor, two hydrophobic, one ring aromatic and one neg ionizable features, Hypo 1 has a correlation coefficient of 0.948, cost difference of 78.894, and RMSD 0.926. This model was validated by test set and Fischer randomization test. Hypo 1 was employed as a 3D query to identify potent molecules from our lab chemical database. Compound 38-C11 had Hypo 1 estimated IC₅₀ of 489 nM. Then 38-C11 was synthesized and evaluated in HsDHODH inhibition assay. The IC₅₀ of 38-C11 was 136.9 nM suggesting that 38-C11 could be proceeded for further evaluation in future study.