In silico and pharmacological screenings identify novel serine racemase inhibitors

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3732-5. doi: 10.1016/j.bmcl.2014.07.003. Epub 2014 Jul 5.

Abstract

D-Serine is a coagonist of the N-methyl-D-aspartate (NMDA)-type glutamate receptor and its biosynthesis is catalyzed by serine racemase (SR). The overactivation of the NMDA receptor has been implicated in the development of neurodegenerative diseases, strokes, and epileptic seizures, thus, the inhibitors of SR have potential against these pathological states. Here, we have developed novel inhibitors of SR by in silico screening and in vitro enzyme assay. The newly developed inhibitors have lower IC50 value comparing with that of malonate, one of the standard SR inhibitor. The structural features of novel inhibitors suggest the importance of central amide structure having a phenoxy substituent in their structure for the SR inhibitory activity. The present findings suggest the importance and rational development of new drugs for diseases of NMDAR overactivation.

Keywords: In silico screening; NMDA receptor; Overactivation; Serine racemase inhibitors; d-Serine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Racemases and Epimerases / antagonists & inhibitors*
  • Racemases and Epimerases / metabolism
  • Structure-Activity Relationship

Substances

  • Amides
  • Enzyme Inhibitors
  • Racemases and Epimerases
  • serine racemase