A novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors

J Am Chem Soc. 2002 Feb 20;124(7):1234-40. doi: 10.1021/ja011239y.


The increasing diversity of small molecule libraries has been an important source for the development of new drugs and, more recently, for unraveling the mechanisms of cellular events-a process termed chemical genetics.(1) Unfortunately, the majority of currently available compounds are mechanism-based enzyme inhibitors, whereas most of cellular activity regulation proceeds on the level of protein-protein interactions. Hence, the development of small molecule inhibitors of protein-protein interactions is important. When screening compound libraries, low-micromolar inhibitors of protein interactions can be routinely found. The enhancement of affinities and rationalization of the binding mechanism require structural information about the protein-ligand complexes. Crystallization of low-affinity complexes is difficult, and their NMR analysis suffers from exchange broadening, which limits the number of obtainable intermolecular constraints. Here we present a novel method of ligand validation and optimization, which is based on the combination of structural and computational approaches. We successfully used this method to analyze the basis for structure-activity relationships of previously selected (2) small molecule inhibitors of the antiapoptotic protein Bcl-xL and identified new members of this inhibitor family.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetates / chemistry
  • Acetates / metabolism
  • Acetates / pharmacology
  • Benzamides / chemistry*
  • Benzamides / metabolism
  • Benzamides / pharmacology
  • Benzylidene Compounds / chemistry*
  • Benzylidene Compounds / metabolism
  • Benzylidene Compounds / pharmacology
  • Drug Evaluation, Preclinical
  • Ligands
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Conformation
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / chemistry*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Structure-Activity Relationship
  • Substrate Specificity
  • bcl-X Protein


  • Acetates
  • Benzamides
  • Benzylidene Compounds
  • Ligands
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein