Structural basis of DNA topoisomerase II-α (Top2-α) inhibition: a computational analysis of interactions between Top2-α and its inhibitors
| Autor: | Mohamad Reza Ganjalikhany, Sadeq Vallian, Moein Dehbashi, Marjan Mojtabavi Naeini, Farzaneh Mohamadi Farsani |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Mitoxantrone biology medicine.drug_class Topoisomerase Organic Chemistry Pharmacology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Enzyme Drug development Biochemistry chemistry Docking (molecular) 030220 oncology & carcinogenesis medicine biology.protein General Pharmacology Toxicology and Pharmaceutics Amsacrine Topoisomerase inhibitor DNA medicine.drug |
| Zdroj: | Medicinal Chemistry Research. 25:1250-1259 |
| ISSN: | 1554-8120 1054-2523 |
| DOI: | 10.1007/s00044-016-1567-1 |
| Popis: | Topoisomerases are enzymes that resolve winding problem of DNA during cellular processes. Because of essential roles of these enzymes in maintenance of cell function, topoisomerases are important targets for cancer chemotherapy. To date, several topoisomerase inhibitors have been introduced and applied as drugs in the treatment of cancer. Topoisomerase II α (Top2-α), a subclass of topoisomerase II enzymes, functions as the target for several anticancer agents and a variety of mutations in this protein have been associated with the development of drug resistance. Mitoxantrone and Amsacrine are among two important inhibitors of Top2 enzymes used in cancer chemotherapy. In this study, we used computational methods to analysis interactions between these compounds and Top2-α in order to identify the most important residues involved in the enzyme inhibition. In order to obtain reliable results, several docking studies have been performed on the human Top2-β to reproduce binding modes which are observed in the crystal form of Top2-β complexed with Mitoxantrone and Amsacrine. Since human Top2-β is the closest homologue to Top2-α, same docking parameters have been used for docking of Top2-α with mentioned drugs. The data also showed that the main residues involved in the interaction between Top2-α and Mitoxantrone were Lys489, Asp504, Glu506, Gly488, Ile490 and Leu491. For Top2α-Amsacrine complex, the interaction was mainly through Arg487, Glu506, Gly488, Lys489, Asn504 and Ala505. These findings clarify the mechanisms of action for these drugs and may facilitate future drug development and cancer treatment. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink