NMR-based Drug Development and Improvement Against Malignant Melanoma – Implications for the MIA Protein Family

Title:NMR-based Drug Development and Improvement Against Malignant Melanoma – Implications for the MIA Protein Family

Volume: 24 Issue: 17

Author(s): Oliver Arnolds, Xueyin Zhong, King Tuo Yip, Miriam Schöpel, Bastian Kohl, Stefanie Pütz, Raid Abdel-Jalil and Raphael Stoll*

Affiliation:

• Biomolecular NMR, Ruhr University of Bochum, 44780 Bochum,Germany

Keywords: NMR, FBLS, MIA, FDP, TANGO, SH3.

Abstract: The Melanoma Inhibitory Activity (MIA) protein is strongly expressed and secreted by malignant melanoma cells and was shown to promote melanoma development and invasion. The MIA protein was the first extracellular protein shown to adopt an Src homology 3 (SH3) domain-like fold in solution that can bind to fibronectin type III domains. Together with MIA, the homologous proteins OTOR (or FDP), MIA-2, and TANGO (or MIA-3) constitute a protein family of non-cytosolic and – except for fulllength TANGO and TANGO1-like (TALI) – extracellular SH3-domain containing proteins. Members of this protein family modulate collagen maturation and export, cartilage development, cell attachment in the extracellular matrix, and melanoma metastasis. These proteins may thus serve as promising targets for drug development against malignant melanoma.

For the last twenty years, NMR spectroscopy has become a powerful technique in medicinal chemistry. While traditional high throughput screenings only report on the activity or affinity of low molecular weight compounds, NMR spectroscopy does not only relate to the structure of those compounds with their activity, but it can also unravel structural information on the ligand binding site on the protein at atomic resolution. Based on the molecular details of the interaction between the ligand and its target protein, the binding affinities of initial fragment hits can be further improved more efficiently in order to generate lead structures that exhibit significant therapeutic effects. The NMR-based approach promises to greatly contribute to the quest for low molecular weight compounds that ultimately could yield drugs to treat skin-related diseases such as malignant melanoma more effectively.

Cite this article as:

Arnolds Oliver , Zhong Xueyin , Tuo Yip King , Schöpel Miriam , Kohl Bastian , Pütz Stefanie, Abdel-Jalil Raid and Stoll Raphael *, NMR-based Drug Development and Improvement Against Malignant Melanoma – Implications for the MIA Protein Family, Current Medicinal Chemistry 2017; 24 (17) . https://dx.doi.org/10.2174/0929867324666170608104347

DOI https://dx.doi.org/10.2174/0929867324666170608104347	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X