Structure-based virtual screening and biological evaluation of potent and selective ADAM12 inhibitors

Bioorg Med Chem Lett. 2004 Dec 20;14(24):6071-4. doi: 10.1016/j.bmcl.2004.09.082.

Abstract

We describe a series of potent and selective inhibitors of ADAM12 that were discovered using computational screening of a focused virtual library. The initial structure-based virtual screening selected 64 compounds from a 3D database of 67,062 molecules. Being evaluated by a cell-based ADAM12 activity assay, compounds 5, 11, 14, 16 were further identified as the potent and selective inhibitors of ADAM12 with low nanomolar IC50 values. The mechanism underlying the potency and selectivity of a representative compound, 5, was investigated through molecular docking studies.

MeSH terms

  • ADAM Proteins
  • ADAM12 Protein
  • Computer-Aided Design
  • Drug Evaluation, Preclinical / methods
  • Membrane Proteins / antagonists & inhibitors*
  • Metalloendopeptidases / antagonists & inhibitors*
  • Models, Biological
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors* / chemistry
  • Protease Inhibitors* / pharmacology
  • Structure-Activity Relationship

Substances

  • Membrane Proteins
  • Protease Inhibitors
  • ADAM Proteins
  • ADAM12 Protein
  • Metalloendopeptidases