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Pharmacophore-Based Discovery of New Human Dihydroorotate Dehydrogenase Inhibitor

[ Vol. 10 , Issue. 4 ]


Peng Lu, Yubin Wang, Bo Ma, Jinxiong She, Qi Zhang, Mingfang He and Ying Liu   Pages 402 - 408 ( 7 )


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.


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


Nanjing Sino-USA Cancer Research Center, School of Pharmaceutical Sciences, Nanjing University of Technology, Nanjing 210009, China.

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