Novel protein-inhibitor interactions in site 3 of Ca(2+)-bound S100B as discovered by X-ray crystallography.
Structure-based drug discovery is under way to identify and develop small-molecule S100B inhibitors (SBiXs). Such inhibitors have therapeutic potential for treating malignant melanoma, since high levels of S100B downregulate wild-type p53 tumor suppressor function in this cancer. Computational and X-ray crystallographic studies of two S100B-SBiX complexes are described, and both compounds (apomorphine hydrochloride and ethidium bromide) occupy an area of the S100B hydrophobic cleft which is termed site 3. These data also reveal novel protein-inhibitor interactions which can be used in future drug-design studies to improve SBiX affinity and specificity. Of particular interest, apomorphine hydrochloride showed S100B-dependent killing in melanoma cell assays, although the efficacy exceeds its affinity for S100B and implicates possible off-target contributions. Because there are no structural data available for compounds occupying site 3 alone, these studies contribute towards the structure-based approach to targeting S100B by including interactions with residues in site 3 of S100B.
Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Michael C
MC
Cavalier
Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Zephan
Z
Melville
Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Ehson
E
Aligholizadeh
Computer Aided Drug Design Center, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
E Prabhu
EP
Raman
Computer Aided Drug Design Center, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
Wenbo
W
Yu
Computer Aided Drug Design Center, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
Lei
L
Fang
Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Milad
M
Alasady
Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Adam D
AD
Pierce
Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Paul T
PT
Wilder
Computer Aided Drug Design Center, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
Alexander D
AD
MacKerell
Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics (CBT), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
David J
DJ
Weber
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008545:Melanoma / Q000188:drug therapy; D062105:Molecular Docking Simulation; D009418:S100 Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009418:S100 Proteins; D054852:Small Molecule Libraries
S100B; X-ray crystallography; drug design; inhibitor; melanoma