Antileishmanial activity mediated by apoptosis and structure-based target study of peganine hydrochloride dihydrate: an approach for rational drug design
| Autor: | Hemanta K. Majumder, Tanvir Khaliq, Souvik Sengupta, Pramod K. Kushawaha, Tadigoppula Narender, Pragya Misra, Awanish Kumar, Anuradha Dube, Shraddha Kumari, Mukesh Samant, Anshuman Dixit, Anil K. Saxena |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Microbiology (medical) Programmed cell death Antiprotozoal Agents Leishmania donovani Drug design Apoptosis Biology Mitochondrion Structure-Activity Relationship chemistry.chemical_compound Alkaloids parasitic diseases Animals Pharmacology (medical) Membrane Potential Mitochondrial Pharmacology Topoisomerase biology.organism_classification Leishmania Protein Structure Tertiary Infectious Diseases chemistry Biochemistry Drug Design Quinazolines biology.protein Topoisomerase I Inhibitors DNA Protein Binding |
| Zdroj: | Journal of Antimicrobial Chemotherapy. 62:998-1002 |
| ISSN: | 1460-2091 0305-7453 |
| DOI: | 10.1093/jac/dkn319 |
| Popis: | Objectives: The aim of this study was to resolve the putative pathway responsible for death induced by peganine hydrochloride dihydrate isolated from Peganum harmala seeds at cellular, structural and molecular level in Leishmania donovani, a causative agent of fatal visceral leishmaniasis. Methods: The mode of action was assessed using various biochemical approaches including phosphatidylserine exposure, estimation of mitochondrial transmembrane potential and in situ dUTP nick end labelling staining of nicked DNA in the parasite. Molecular modelling and molecular dynamics studies were conducted with DNA topoisomerase I to identify the target of peganine hydrochloride dihydrate mediating apoptosis. Further, DNA topoisomerase I inhibition by peganine hydrochloride dihydrate was also assessed using an L. donovani topoisomerase I relaxation assay. Results: Peganine hydrochloride dihydrate, besides being safe, was found to induce apoptosis in both the stages of L. donovani via loss of mitochondrial transmembrane potential. Molecular docking studies suggest that a binding interaction with DNA topoisomerase I of L. donovani (binding energy of 279 kcal/mol) forms a stable complex, indicating a possible role in apoptosis. The compound also inhibits L. donovani topoisomerase I. Conclusions: The compound induces apoptosis in L. donovani and inhibits DNA topoisomerase I. |
| Databáze: | OpenAIRE |
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