Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations

  • J Med Chem. 2016 Jan 28;59(2):592-608. doi: 10.1021/acs.jmedchem.5b01369.
Michael C Cavalier  1 ,  Mohd Imran Ansari  2 ,  Adam D Pierce  1 ,  Paul T Wilder  1  3 ,  Laura E McKnight  1 ,  E Prabhu Raman  2 ,  David B Neau  4 ,  Padmavani Bezawada  2 ,  Milad J Alasady  1 ,  Thomas H Charpentier  1 ,  Kristen M Varney  1 ,  Eric A Toth  1  3  5 ,  Alexander D MacKerell Jr  3  2 ,  Andrew Coop  3  2 ,  David J Weber  1  3
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
  • 2. Computer Aided Drug Design Center, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
  • 3. Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
  • 4. NE-CAT , Argonne Illinois 60439, United States.
  • 5. Institute for Bioscience and Biotechnology Research , 9600 Gudelsky Drive, Rockville, Maryland 20850, United States.
PMID: 26727270 DOI: 10.1021/acs.jmedchem.5b01369
Abstract

The drug pentamidine inhibits calcium-dependent complex formation with p53 ((CA)S100B·p53) in malignant melanoma (MM) and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure-activity relationship (SAR) studies were therefore completed here with 23 pentamidine analogues, and X-ray structures of (CA)S100B·inhibitor complexes revealed that the C-terminus of S100B adopts two different conformations, with location of Phe87 and Phe88 being the distinguishing feature and termed the "FF-gate". For symmetric pentamidine analogues ((CA)S100B·5a, (CA)S100B·6b) a channel between sites 1 and 2 on S100B was occluded by residue Phe88, but for an asymmetric pentamidine analogue ((CA)S100B·17), this same channel was open. The (CA)S100B·17 structure illustrates, for the first time, a pentamidine analog capable of binding the "open" form of the "FF-gate" and provides a means to block all three "hot spots" on (CA)S100B, which will impact next generation (CA)S100B·p53 inhibitor design.