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Specificity of Molecular Fragments Binding to S100B versus S100A1 as Identified by NMR and Site Identification by Ligand Competitive Saturation (SILCS).

ABSTRACT: S100B, 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.

SUBMITTER: Young BD

PROVIDER: S-EPMC7828390 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Specificity of Molecular Fragments Binding to S100B versus S100A1 as Identified by NMR and Site Identification by Ligand Competitive Saturation (SILCS).

Young Brianna D BD Yu Wenbo W Rodríguez Darex J Vera DJV Varney Kristen M KM MacKerell Alexander D AD Weber David J DJ

Molecules (Basel, Switzerland) 20210113 2

S100B, 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 fo ...[more]

PMID: 33450915

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Project description:BackgroundFragment-based ligand design is used for the development of novel ligands that target macromolecules, most notably proteins. Central to its success is the identification of fragment binding sites that are spatially adjacent such that fragments occupying those sites may be linked to create drug-like ligands. Current experimental and computational approaches that address this problem typically identify only a limited number of sites as well as use a limited number of fragment types.MethodsThe site-identification by ligand competitive saturation (SILCS) approach is extended to the identification of fragment bindings sites, with the method termed SILCS-Hotspots. The approach involves precomputation of the SILCS FragMaps following which the identification of Hotspots, performed by identifying of all possible fragment binding sites on the full 3D structure of the protein followed by spatial clustering.ResultsThe SILCS-Hotspots approach identifies a large number of sites on the target protein, including many sites not accessible in experimental structures due to low binding affinities and binding sites on the protein interior. The identified sites are shown to recapitulate the location of known drug-like molecules in both allosteric and orthosteric binding sites on seven proteins including the androgen receptor, the CDK2 and Erk5 kinases, PTP1B phosphatase and three GPCRs; the β2-adrenergic, GPR40 fatty-acid binding and M2-muscarinic receptors. Analysis indicates the importance of considering all possible fragment binding sites, and not just those accessible to experimental methods, when identifying novel binding sites and performing ligand design versus just considering the most favorable sites. The approach is shown to identify a larger number of known binding sites of drug-like molecules versus the commonly used FTMap and Fpocket methods.General significanceThe present results indicate the potential utility of the SILCS-Hotspots approach for fragment-based rational design of ligands, including allosteric modulators.

Dataset Information

Specificity of Molecular Fragments Binding to S100B versus S100A1 as Identified by NMR and Site Identification by Ligand Competitive Saturation (SILCS).

Publications

Specificity of Molecular Fragments Binding to S100B versus S100A1 as Identified by NMR and Site Identification by Ligand Competitive Saturation (SILCS).

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