Trapping moving targets with small molecules

Science. 2009 Apr 10;324(5924):213-5. doi: 10.1126/science.1169378.

Abstract

Structure-based drug design traditionally uses static protein models as inspirations for focusing on "active" site targets. Allosteric regulation of biological macromolecules, however, is affected by both conformational and dynamic properties of the protein or protein complex and can potentially lead to more avenues for therapeutic development. We discuss the advantages of searching for molecules that conformationally trap a macromolecule in its inactive state. Although multiple methodologies exist to probe protein dynamics and ligand binding, our current discussion highlights the use of nuclear magnetic resonance spectroscopy in the drug discovery and design process.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Apoproteins / chemistry
  • Apoproteins / metabolism
  • Benzamides
  • CREB-Binding Protein / chemistry
  • CREB-Binding Protein / metabolism
  • Catalytic Domain
  • Cyclic AMP Response Element-Binding Protein / chemistry
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Drug Design*
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Imatinib Mesylate
  • Ligands
  • Nuclear Magnetic Resonance, Biomolecular
  • Piperazines / metabolism
  • Piperazines / pharmacology
  • Protein Binding
  • Protein Conformation*
  • Protein Multimerization
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proteins / antagonists & inhibitors
  • Proteins / chemistry*
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology
  • Signal Transduction
  • Small Molecule Libraries
  • Thermodynamics
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Apoproteins
  • Benzamides
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Ligands
  • Piperazines
  • Proteins
  • Pyrimidines
  • Small Molecule Libraries
  • Tumor Suppressor Protein p53
  • Imatinib Mesylate
  • CREB-Binding Protein
  • Proto-Oncogene Proteins c-mdm2
  • Protein-Tyrosine Kinases