2. Academic Validation
  3. Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations

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

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.

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