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JAC Advance Access originally published online on August 11, 2008
Journal of Antimicrobial Chemotherapy 2008 62(5):998-1002; doi:10.1093/jac/dkn319
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Antileishmanial activity mediated by apoptosis and structure-based target study of peganine hydrochloride dihydrate: an approach for rational drug design

Pragya Misra1, Tanvir Khaliq2, Anshuman Dixit2, Souvik SenGupta3, Mukesh Samant1, Shraddha Kumari1, Awanish Kumar1, Pramod K. Kushawaha1, H. K. Majumder3, Anil K. Saxena2, T. Narender2 and Anuradha Dube1,*

1 Division of Parasitology, Central Drug Research Institute, Lucknow 226001, India 2 Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226001, India 3 Department of Molecular Parasitology, Indian Institute of Chemical Biology, Kolkata 700032, India

Received 4 April 2008; returned 9 May 2008; revised 27 June 2008; accepted 30 June 2008

* Corresponding author. Tel: +91-522-2612411; Fax: +91-522-2623405; E-mail: anuradha_dube{at}rediffmail.com

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 –79 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.

Keywords: apoptosis , mitochondrial transmembrane potential , TUNEL assay , molecular docking


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