Identification of potential Mycobacterium tuberculosis topoisomerase I inhibitors: A study against active, dormant and resistant tuberculosis
| Autor: | Renuka Janupally, Vijay Soni, Hasitha Shilpa Anantaraju, Dharmarajan Sriram, Priyanka Suryadevara, Jogula Sridhar, Jonnalagadda Padma Sridevi, Perumal Yogeeswari |
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| Rok vydání: | 2015 |
| Předmět: |
Cell Survival
Antitubercular Agents Pharmaceutical Science Molecular Dynamics Simulation Topoisomerase-I Inhibitor Mycobacterium Microbiology Mycobacterium tuberculosis Biological pathway Bacterial Proteins Drug Resistance Bacterial medicine Animals Humans Pathogen Zebrafish chemistry.chemical_classification Mycobacterium Infections biology Topoisomerase Isoniazid biology.organism_classification Protein Structure Tertiary Molecular Docking Simulation HEK293 Cells Enzyme DNA Topoisomerases Type I chemistry Biochemistry biology.protein DNA supercoil Camptothecin Topoisomerase I Inhibitors medicine.drug |
| Zdroj: | European Journal of Pharmaceutical Sciences. 72:81-92 |
| ISSN: | 0928-0987 |
| DOI: | 10.1016/j.ejps.2015.02.017 |
| Popis: | Mycobacterium tuberculosis (Mtb) topoisomerase I (Topo I), involved in the relaxation of negatively supercoiled DNA, plays an important role in the viability of pathogen Mtb. Being one of the most significant enzymes; it also takes part in crucial biological pathways such as transcription and replication of the pathogen. The present study aims at the development of Mtb Topo I 3D protein structure which in turn was employed for the virtual screening of compound libraries in a process of identification of a hit molecule. The identified hit, hydroxycamptothecin, was active at 6.25 μM which was further derivatized synthetically into fifteen novel analogues. Among these, four compounds (3b, 3g, 3h and 3l) emerged to be active displaying IC50 values ranging from 2.9 to 9.3 μM against Mtb Topo I and were non-cytotoxic at 25 μM. These four compounds also proved their efficacy when tested against active, dormant and resistant forms of Mtb. The most potent inhibitor 3b was screened for in vivo anti-mycobacterial activity using zebrafish model and was found to be more effective when compared to first line anti-tubercular drugs, isoniazid and rifampicin. The binding affinity of this compound towards Mtb Topo I was analyzed by differential scanning fluorimetry which resulted in a positive shift in melting temperature when compared to the native protein thereby proving its stabilization effect over protein. |
| Databáze: | OpenAIRE |
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