Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators
| Autor: | Masaru Miyagi, Suheel K. Porwal, Chris Dealwis, Andrew Zhang, Michael E. Harris, Rajesh Viswanathan, Tessianna A. Misko, Kay Perry, John J. Pink, Nancy L. Oleinick, Intekhab Alam, Md. Faiz Ahmad, Sarah E. Huff |
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| Rok vydání: | 2015 |
| Předmět: |
Ribonucleoside Diphosphate Reductase
Protein Conformation Stereochemistry Antineoplastic Agents Phthalimides Plasma protein binding Random hexamer Crystallography X-Ray Article Phthalimide Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Ribonucleotide Reductases Drug Discovery Humans Structure–activity relationship Computer Simulation Cell Proliferation chemistry.chemical_classification Tumor Suppressor Proteins Small molecule Molecular Docking Simulation Enzyme Ribonucleotide reductase chemistry Biochemistry Molecular Medicine Drug Screening Assays Antitumor Protein Multimerization Nucleoside Databases Chemical Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 58:9498-9509 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.5b00929 |
| Popis: | Ribonucleotide reductase (RR) catalyzes the rate-limiting step of dNTP synthesis and is an established cancer target. Drugs targeting RR are mainly nucleoside in nature. In this study, we sought to identify non-nucleoside small-molecule inhibitors of RR. Using virtual screening, binding affinity, inhibition, and cell toxicity, we have discovered a class of small molecules that alter the equilibrium of inactive hexamers of RR, leading to its inhibition. Several unique chemical categories, including a phthalimide derivative, show micromolar IC50s and KDs while demonstrating cytotoxicity. A crystal structure of an active phthalimide binding at the targeted interface supports the noncompetitive mode of inhibition determined by kinetic studies. Furthermore, the phthalimide shifts the equilibrium from dimer to hexamer. Together, these data identify several novel non-nucleoside inhibitors of human RR which act by stabilizing the inactive form of the enzyme. |
| Databáze: | OpenAIRE |
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