jm7b00089_si_005.csv (1.43 kB)
Exploring Heme and Hemoglobin Binding Regions of Plasmodium Heme Detoxification Protein for New Antimalarial Discovery
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posted on 2017-09-26, 00:00 authored by Priya Gupta, Sonali Mehrotra, Anil Sharma, Monika Chugh, Rajan Pandey, Abhinav Kaushik, Sachin Khurana, Neha Srivastava, Tarushikha Srivastava, Arunaditya Deshmukh, Ashutosh Panda, Priyanka Aggarwal, Neel Sarovar Bhavesh, Raj K. Bhatnagar, Asif Mohmmed, Dinesh Gupta, Pawan MalhotraHemoglobin
degradation/hemozoin formation, essential steps in the Plasmodium life cycle, are targets of existing antimalarials.
The pathway still offers vast possibilities to be explored for new
antimalarial discoveries. Here, we characterize heme detoxification
protein, PfHDP, a major protein involved in hemozoin
formation, as a novel drug target. Using in silico and biochemical
approaches, we identified two heme binding sites and a hemoglobin
binding site in PfHDP. Treatment of Plasmodium falciparum 3D7 parasites with peptide
corresponding to the hemoglobin binding domain in PfHDP resulted in food vacuole abnormalities similar to that seen with
a cysteine protease inhibitor, E-64 (I-1). Screening of compounds
that bound the modeled PfHDP structure in the heme/hemoglobin-binding
pockets from Maybridge Screening Collection identified a compound,
ML-2, that inhibited parasite growth in a dose-dependent manner, thus
paving the way for testing its potential as a new drug candidate.
These results provide functional insights into the role of PfHDP in Hz formation and further suggest that PfHDP could be an important drug target to combat malaria.
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hemoglobin binding domainMaybridge Screening Collectioncysteine protease inhibitorPlasmodium Heme Detoxification Proteinformationfood vacuole abnormalitiesPlasmodium life cycleMLheme binding sitesHemoglobin Binding RegionsPlasmodium falciparum 3 D 7 parasitesPf HDP structurenovel drug targetheme detoxification proteinhemoglobin binding sitePf HDP
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