In silico derived small molecules targeting the finger-finger interaction between the histone lysine methyltransferase NSD1 and Nizp1 repressor
| Autor: | Andrea Berardi, Michela Ghitti, Giovanna Musco, Giacomo Quilici |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Virtual screening
Protein-protein interactions lcsh:Biotechnology Protein domain VS Virtual Screening STD saturation transfer difference Biophysics Druggability PHD finger Computational biology NMR Nuclear Magnetic Resonance Biochemistry NSD1 Protein–protein interaction PHD finger Plant Homeodomain finger Nizp1 (NSD1-interacting Zn-finger protein) 03 medical and health sciences 0302 clinical medicine Structural Biology lcsh:TP248.13-248.65 Genetics 030304 developmental biology Histone binding ComputingMethodologies_COMPUTERGRAPHICS Zinc finger 0303 health sciences C2HRNizp1 C2HR finger domain of Nizp1 Chemistry NSD1 Nuclear receptor-binding SET (Su(var)3–9 Enhancer of zeste Trithorax) domain protein 1 Chromatin binding NMR Computer Science Applications 030220 oncology & carcinogenesis PHDVC5HCHNSD1 Fifth PHD and C5HCH tandem domain of NSD1 Nizp1 Biotechnology Research Article |
| Zdroj: | Computational and Structural Biotechnology Journal Computational and Structural Biotechnology Journal, Vol 18, Iss, Pp 4082-4092 (2020) |
| ISSN: | 2001-0370 |
| Popis: | Graphical abstract PHD fingers are small chromatin binding domains, that alone or in tandem work as versatile interaction platforms for diversified activities, ranging from the decoding of the modification status of histone tails to the specific recognition of non-histone proteins. They play a crucial role in their host protein as mutations thereof cause several human malignancies. Thus, PHD fingers are starting to be considered as valuable pharmacological targets. While inhibitors or chemical probes of the histone binding activity of PHD fingers are emerging, their druggability as non-histone interaction platform is still unexplored. In the current study, using a computational and experimental pipeline, we provide proof of concept that the tandem PHD finger of Nuclear receptor-binding SET (Su(var)3–9, Enhancer of zeste, Trithorax) domain protein 1 (PHDVC5HCHNSD1) is ligandable. Combining virtual screening of a small subset of the ZINC database (Zinc Drug Database, ZDD, 2924 molecules) to NMR binding assays and ITC measurements, we have identified Mitoxantrone dihydrochloride, Quinacrine dihydrochloride and Chloroquine diphosphate as the first molecules able to bind to PHDVC5HCHNSD1 and to reduce its documented interaction with the Zinc finger domain (C2HRNizp1) of the transcriptional repressor Nizp1 (NSD1-interacting Zn-finger protein). These results pave the way for the design of small molecules with improved effectiveness in inhibiting this finger-finger interaction. |
| Databáze: | OpenAIRE |
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