Novel protein-inhibitor interactions in site 3 of Ca2+-bound S100B as discovered by X-ray crystallography:

Abstract

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.A structure-based drug-discovery program is under way in order to identify and develop small-molecule inhibitors of S100B for the treatment of malignant melanoma. X-ray crystallographic analysis of two S100B inhibitors reveals newly identified inhibitor-target interactions within site 3 of Ca2+-bound S100B. These data contribute to the structural biology knowledge base for this target, which is important for rational drug-design efforts.