Pharmacophore-based discovery of new human dihydroorotate dehydrogenase inhibitor

Peng Lu, Yubin Wang, Bo Ma, Jinxiong She, Qi Zhang, Mingfang He, Ying Liu

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)402-408
Number of pages7
JournalMedicinal Chemistry
Volume10
Issue number4
DOIs
Publication statusPublished - Jun 2014
Externally publishedYes

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Keywords

  • Discovery studio
  • Drug discovery
  • Human DHODH inhibitor
  • HypoGen
  • Pharmacophore
  • Virtual screening

ASJC Scopus subject areas

  • Drug Discovery

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