In silico-guided target identification of a scaffold-focused library: 1,3,5-triazepan-2,6-diones as novel phospholipase A2 inhibitors

J Med Chem. 2006 Nov 16;49(23):6768-78. doi: 10.1021/jm0606589.

Abstract

A collection of 2150 druggable active sites from the Protein Data Bank was screened by high-throughput docking to identify putative targets for five representative molecules of a combinatorial library sharing a 1,3,5-triazepan-2,6-dione scaffold. Five targets were prioritized for experimental evaluation by computing enrichment in individual protein entries among the top 2% scoring targets. Out of the five proposed proteins, secreted phospholipase A2 (sPLA2) was shown to be a true target for a panel of 1,3,5-triazepan-2,6-diones which exhibited micromolar affinities toward two human sPLA2 members.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azepines / chemical synthesis
  • Azepines / chemistry*
  • Azepines / pharmacology
  • Binding Sites
  • Combinatorial Chemistry Techniques
  • Databases, Factual*
  • Databases, Protein
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / enzymology
  • Humans
  • Models, Molecular
  • Phospholipases A / antagonists & inhibitors*
  • Phospholipases A / chemistry
  • Phospholipases A2
  • Structure-Activity Relationship

Substances

  • Azepines
  • Enzyme Inhibitors
  • Phospholipases A
  • Phospholipases A2