Development of MTH1-Binding Nucleotide Analogs Based on 7,8-Dihalogenated 7-Deaza-dG Derivatives
| Autor: | Shigeki Sasaki, Ren Ishikawa, Choon Han Heh, Yosuke Taniguchi, Hui Shi |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Protein Conformation
alpha-Helical 0301 basic medicine Halogenation 01 natural sciences Substrate Specificity Nucleobase lcsh:Chemistry heterocyclic compounds Nucleotide lcsh:QH301-705.5 Spectroscopy chemistry.chemical_classification biology Chemistry Hydrolysis Deoxyguanine Nucleotides General Medicine dihalogenated nucleoside derivative MTH1 Computer Science Applications Molecular Docking Simulation Protein Binding nucleotide analog Stereochemistry Article Catalysis Inorganic Chemistry Structure-Activity Relationship 03 medical and health sciences Humans Protein Interaction Domains and Motifs Physical and Theoretical Chemistry Molecular Biology Enzyme Assays Binding Sites 010405 organic chemistry Molecular Mimicry Organic Chemistry Substrate (chemistry) Active site Phosphoric Monoester Hydrolases Enzyme assay oxidized nucleotide 0104 chemical sciences Kinetics Oxidative Stress genomic DNA DNA Repair Enzymes 030104 developmental biology Enzyme lcsh:Biology (General) lcsh:QD1-999 Docking (molecular) Drug Design biology.protein Protein Conformation beta-Strand DNA Damage |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 1274, p 1274 (2021) International Journal of Molecular Sciences Volume 22 Issue 3 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22031274 |
| Popis: | MTH1 is an enzyme that hydrolyzes 8-oxo-dGTP, which is an oxidatively damaged nucleobase, into 8-oxo-dGMP in nucleotide pools to prevent its mis-incorporation into genomic DNA. Selective and potent MTH1-binding molecules have potential as biological tools and drug candidates. We recently developed 8-halogenated 7-deaza-dGTP as an 8-oxo-dGTP mimic and found that it was not hydrolyzed, but inhibited enzyme activity. To further increase MTH1 binding, we herein designed and synthesized 7,8-dihalogenated 7-deaza-dG derivatives. We successfully synthesized multiple derivatives, including substituted nucleosides and nucleotides, using 7-deaza-dG as a starting material. Evaluations of the inhibition of MTH1 activity revealed the strong inhibitory effects on enzyme activity of the 7,8-dihalogenated 7-deaza-dG derivatives, particularly 7,8-dibromo 7-daza-dGTP. Based on the results obtained on kinetic parameters and from computational docking simulating studies, these nucleotide analogs interacted with the active site of MTH1 and competitively inhibited the substrate 8-oxodGTP. Therefore, novel properties of repair enzymes in cells may be elucidated using new compounds. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|