In silico studies and evaluation of antiparasitic role of a novel pyruvate phosphate dikinase inhibitor in Leishmania donovani infected macrophages

Mohammad Kashif, Sumit Kumar Hira, Anurag Upadhyaya, Uttam Gupta, Ranjeet Singh, Ankush Paladhi, Faez Iqbal Khan, Abdur Rub, Partha Pratim Manna*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

The present work deals with the identification and characterization of a novel inhibitor Z220582104, specific to pyruvate phosphate dikinase, for leishmanicidal activities against free promastigotes and intracellular amastigotes. We have used structure-based drug designing approaches and performed homology modelling, virtual screening and molecular dynamics studies. Primary mouse macrophages and macrophage cell line J774A1 were infected with promastigotes of Leishmania donovani. Both promastigotes and infected macrophages were subjected to treatment with the varying concentrations of Z220582104 or miltefosine for assessment of leishmanicidal activity. The novel inhibitor Z220582104 demonstrated growth inhibitory potential and reduced the viability of the free promastigotes in a concentration- and time-dependent manner. Z220582104 was also effective against the intracellular form of the parasites and reduced the number of amastigotes in macrophages and also lowered the parasite index, compared with the untreated infected macrophages. Although less effective compared with the miltefosine, Z220582104 is well tolerated by the dividing cells and normal human lymphocytes and monocytes with no adverse effects on the growth kinetics or viability. Our in silico and in vitro studies suggested that Leishmania donovani pyruvate phosphate dikinase could be a potential new drug target.

Original languageEnglish
Pages (from-to)508-514
Number of pages7
JournalInternational Journal of Antimicrobial Agents
Volume53
Issue number4
DOIs
Publication statusPublished - Apr 2019
Externally publishedYes

Keywords

  • Drug design
  • In silico
  • Leishmania
  • Miltefosine
  • Pyruvate phosphate dikinase
  • Z220582104

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