2. Academic Validation
  3. Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase

Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase

  • Bioorg Med Chem Lett. 2013 Jun 1;23(11):3186-94. doi: 10.1016/j.bmcl.2013.04.001.
Peter S Dragovich 1,  Benjamin P Fauber,  Laura B Corson,  Charles Z Ding,  Charles Eigenbrot,  HongXiu Ge,  Anthony M Giannetti,  Thomas Hunsaker,  Sharada Labadie,  Yichin Liu,  Shiva Malek,  Borlan Pan,  David Peterson,  Keith Pitts,  Hans E Purkey,  Steve Sideris,  Mark Ultsch,  Erica VanderPorten,  BinQing Wei,  Qing Xu,  Ivana Yen,  Qin Yue,  Huihui Zhang,  Xuying Zhang
Affiliations

Affiliation

PMID: 23628333 DOI: 10.1016/j.bmcl.2013.04.001
Abstract

A novel 2-thio-6-oxo-1,6-dihydropyrimidine-containing inhibitor of human Lactate Dehydrogenase (LDH) was identified by high-throughput screening (IC50=8.1 μM). Biochemical, surface plasmon resonance, and saturation transfer difference NMR experiments indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of the screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.48 μM). A crystal structure of an optimized compound bound to human LDHA was obtained and explained many of the observed structure-activity relationships.

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