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dc.contributor.authorYoung, Brianna D
dc.contributor.authorYu, Wenbo
dc.contributor.authorRodríguez, Darex J Vera
dc.contributor.authorVarney, Kristen M
dc.contributor.authorMacKerell, Alexander D
dc.contributor.authorWeber, David J
dc.date.accessioned2021-02-08T20:49:01Z
dc.date.available2021-02-08T20:49:01Z
dc.date.issued2021-01-13
dc.identifier.urihttp://hdl.handle.net/10713/14638
dc.description.abstractS100B, a biomarker of malignant melanoma, interacts with the p53 protein and diminishes its tumor suppressor function, which makes this S100 family member a promising therapeutic target for treating malignant melanoma. However, it is a challenge to design inhibitors that are specific for S100B in melanoma versus other S100-family members that are important for normal cellular activities. For example, S100A1 is most similar in sequence and structure to S100B, and this S100 protein is important for normal skeletal and cardiac muscle function. Therefore, a combination of NMR and computer aided drug design (CADD) was used to initiate the design of specific S100B inhibitors. Fragment-based screening by NMR, also termed "SAR by NMR," is a well-established method, and was used to examine spectral perturbations in 2D [1H, 15N]-HSQC spectra of Ca2+-bound S100B and Ca2+-bound S100A1, side-by-side, and under identical conditions for comparison. Of the 1000 compounds screened, two were found to be specific for binding Ca2+-bound S100A1 and four were found to be specific for Ca2+-bound S100B, respectively. The NMR spectral perturbations observed in these six data sets were then used to model how each of these small molecule fragments showed specificity for one S100 versus the other using a CADD approach termed Site Identification by Ligand Competitive Saturation (SILCS). In summary, the combination of NMR and computational approaches provided insight into how S100A1 versus S100B bind small molecules specifically, which will enable improved drug design efforts to inhibit elevated S100B in melanoma. Such a fragment-based approach can be used generally to initiate the design of specific inhibitors for other highly homologous drug targets.en_US
dc.description.urihttps://doi.org/10.3390/molecules26020381en_US
dc.language.isoenen_US
dc.publisherMDPI AGen_US
dc.relation.ispartofMolecules (Basel, Switzerland)en_US
dc.subjectNMRen_US
dc.subjectS100A1en_US
dc.subjectS100Ben_US
dc.subjectSILCSen_US
dc.subjectcalciumen_US
dc.titleSpecificity of Molecular Fragments Binding to S100B versus S100A1 as Identified by NMR and Site Identification by Ligand Competitive Saturation (SILCS)en_US
dc.typeArticleen_US
dc.identifier.doi10.3390/molecules26020381
dc.identifier.pmid33450915
dc.source.volume26
dc.source.issue2
dc.source.countryUnited States
dc.source.countrySwitzerland


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