Design, synthesis, and computational studies of inhibitors of Bcl-XL

J Am Chem Soc. 2006 Dec 20;128(50):16206-12. doi: 10.1021/ja0650347.


One of the primary objectives in the design of protein inhibitors is to shape the three-dimensional structures of small molecules to be complementary to the binding site of a target protein. In the course of our efforts to discover potent inhibitors of Bcl-2 family proteins, we found a unique folded conformation adopted by tethered aromatic groups in the ligand that significantly enhanced binding affinity to Bcl-XL. This finding led us to design compounds that were biased by nonbonding interactions present in a urea tether to adopt this bioactive, folded motif. To characterize the key interactions that induce the desired conformational bias, a series of substituted N,N'-diarylureas were prepared and analyzed using X-ray crystallography and quantum mechanical calculations. Stabilizing pi-stacking interactions and destabilizing steric interactions were predicted to work in concert in two of the substitution patterns to promote the bioactive conformation as a global energy minimum and result in a high target binding affinity. Conversely, intramolecular hydrogen bonding present in the third substitution motif promotes a less active, extended conformer as the energetically favored geometry. These findings were corroborated when the inhibition constant of binding to Bcl-XL was determined for fully elaborated analogues bearing these structural motifs. Finally, we obtained the NMR solution structure of the disubstituted N,N'-diarylurea bound to Bcl-XL demonstrating the folded conformation of the urea motif engaged in extensive pi-interactions with the protein.

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Drug Design*
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Protein Structure, Tertiary
  • bcl-X Protein / antagonists & inhibitors*
  • bcl-X Protein / chemistry
  • bcl-X Protein / metabolism


  • Ligands
  • bcl-X Protein