Identification of Asiaticoside from Centella erecta (Apiaceae) as Potential Apyrase Inhibitor by UF-UHPLC-MS and Its In Vivo Antischistosomal Activity

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Abstract

Schistosomiasis, caused by parasites of the genus Schistosoma, is a neglected disease with high global prevalence, affecting more than 240 million people in several countries. Praziquantel (PZQ) is the only drug currently available for the treatment. S. mansoni NTPDases (known as SmNTPDases, ATP diphosphohydrolases or ecto-apyrases) are potential drug targets for the discovery of new antischistosomal drugs. In this study, we screen NTPDases inhibitors from Centella erecta (Apiaceae) using an ultrafiltration combined UHPLC-QTOF-MS method and potato apyrase, identifying asiaticoside as one of the apyrase-binding compounds. After isolation of asiaticoside from C. erecta extract, we assessed its in vivo antischistosomal activities against Schistosoma mansoni worms and its in vitro enzymatic apyrase inhibition. Also, molecular docking analysis of asiaticoside against potato apyrase, S. mansoni NTPDases 1 and 2 were performed. Asiaticoside showed a significant in vitro apyrase inhibition and molecular docking studies corroborate with its possible actions in potato apyrase and S. mansoni NTPDases. In mice harboring a patent S. mansoni infection, a single oral dose of asiaticoside (400 mg/kg. p.o.) showed significantly in vivo antischistosomal efficacy, markedly decreasing the total worm load and egg burden, giving support for further exploration of apyrase inhibitors as antischistosomal agents.

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AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.

Oleg Trott, Arthur J Olson (2010)

AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user. Copyright 2009 Wiley Periodicals, Inc.

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Bernd M Sanner (1999)

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Human schistosomiasis.

Bruno Gryseels, Katja Polman, Jan Clerinx … (2006)

Schistosomiasis or bilharzia is a tropical disease caused by worms of the genus Schistosoma. The transmission cycle requires contamination of surface water by excreta, specific freshwater snails as intermediate hosts, and human water contact. The main disease-causing species are S haematobium, S mansoni, and S japonicum. According to WHO, 200 million people are infected worldwide, leading to the loss of 1.53 million disability-adjusted life years, although these figures need revision. Schistosomiasis is characterised by focal epidemiology and overdispersed population distribution, with higher infection rates in children than in adults. Complex immune mechanisms lead to the slow acquisition of immune resistance, though innate factors also play a part. Acute schistosomiasis, a feverish syndrome, is mostly seen in travellers after primary infection. Chronic schistosomal disease affects mainly individuals with long-standing infections in poor rural areas. Immunopathological reactions against schistosome eggs trapped in the tissues lead to inflammatory and obstructive disease in the urinary system (S haematobium) or intestinal disease, hepatosplenic inflammation, and liver fibrosis (S mansoni, S japonicum). The diagnostic standard is microscopic demonstration of eggs in the excreta. Praziquantel is the drug treatment of choice. Vaccines are not yet available. Great advances have been made in the control of the disease through population-based chemotherapy but these required political commitment and strong health systems.