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.
Keywords: Human DHODH inhibitor, discovery studio, drug discovery, hypoGen, pharmacophore, virtual screening.
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