Next Article in Journal
Recent Advances in Nanomedicine for the Diagnosis and Treatment of Prostate Cancer Bone Metastasis
Next Article in Special Issue
Tissue mRNA for S100A4, S100A6, S100A8, S100A9, S100A11 and S100P Proteins in Colorectal Neoplasia: A Pilot Study
Previous Article in Journal
The Application of NMR Spectroscopy and Chemometrics in Authentication of Spices
Previous Article in Special Issue
Calcium-Dependent Translocation of S100B Is Facilitated by Neurocalcin Delta
Open AccessArticle

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

1
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene St., Baltimore, MD 21201, USA
2
Center for Biomolecular Therapeutics (CBT), Baltimore, MD 21201, USA
3
Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA
4
Institute for Bioscience and Biotechnology Research (IBBR), Rockville, MD 20850, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Brullo Chiara
Molecules 2021, 26(2), 381; https://doi.org/10.3390/molecules26020381
Received: 22 December 2020 / Revised: 8 January 2021 / Accepted: 9 January 2021 / Published: 13 January 2021
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. View Full-Text
Keywords: S100B; S100A1; calcium; NMR; SILCS S100B; S100A1; calcium; NMR; SILCS
Show Figures

Figure 1

MDPI and ACS Style

Young, B.D.; Yu, W.; Rodríguez, D.J.V.; Varney, K.M.; MacKerell, A.D., Jr.; Weber, D.J. Specificity of Molecular Fragments Binding to S100B versus S100A1 as Identified by NMR and Site Identification by Ligand Competitive Saturation (SILCS). Molecules 2021, 26, 381.

AMA Style

Young BD, Yu W, Rodríguez DJV, Varney KM, MacKerell AD Jr., Weber DJ. Specificity of Molecular Fragments Binding to S100B versus S100A1 as Identified by NMR and Site Identification by Ligand Competitive Saturation (SILCS). Molecules. 2021; 26(2):381.

Chicago/Turabian Style

Young, Brianna D.; Yu, Wenbo; Rodríguez, Darex J.V.; Varney, Kristen M.; MacKerell, Alexander D., Jr.; Weber, David J. 2021. "Specificity of Molecular Fragments Binding to S100B versus S100A1 as Identified by NMR and Site Identification by Ligand Competitive Saturation (SILCS)" Molecules 26, no. 2: 381.

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop