Antileishmanial Activity Mediated by Apoptosis and Structure-based Target Study of Peganine Hydrochloride Dihydrate: An Approach for rational drug design
IR@IICB: CSIR-Indian Institute of Chemical Biology, KolkataView Archive Info
Antileishmanial Activity Mediated by Apoptosis and Structure-based Target Study of Peganine Hydrochloride Dihydrate: An Approach
for rational drug design
Kushawaha, Pramod K
Majumder, Hemanta K
Saxena, Anil K
Infectious Diseases and Immunology
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.
Misra, Pragya and Khaliq, Tanvir and Dixit, Anshuman and SenGupta, Souvik and Samanta, Mukesh and Kumari, Shraddha and Kumar, Awanish and Kushawaha, Pramod K and Majumder, Hemanta K and Saxena, Anil K and Narender, T and Dube, Anuradha (2008) Antileishmanial Activity Mediated by Apoptosis and Structure-based Target Study of Peganine Hydrochloride Dihydrate: An Approach for rational drug design. Journal of Antimicrobial Chemotherapy, 62. pp. 998-1002.