Pharmacophore-Based Discovery of New Human Dihydroorotate Dehydrogenase Inhibitor

Author(s): Peng Lu, Yubin Wang, Bo Ma, Jinxiong She, Qi Zhang, Mingfang He, Ying Liu.

Journal Name: Medicinal Chemistry

Volume 10 , Issue 4 , 2014

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Abstract:

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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Article Details

VOLUME: 10
ISSUE: 4
Year: 2014
Page: [402 - 408]
Pages: 7
DOI: 10.2174/15734064113096660047
Price: $58

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