Drug repurposing for schistosomiasis: molecular docking and dynamics investigations.

Schistosomiasis is a neglected disease of considerable health importance in tropical and subtropical regions. Its treatment relies on the use of praziquantel or oxamniquine but there are reported cases of treatment failures due to resistance or tolerance. Again, derivatives of praziquantel and oxamniquine have not shown significant activities than their parent compounds. The study predicted approved drugs with possible antischistosomal activities. Four schistosomal drug targets were obtained from Protein Data Bank and six hundred and twelve (612) approved drugs including their isomers were selected based on their Molinspiration® bioscore similarities with reference compounds (praziquantel, oxamniquine, [(2S,3S,4S,5S,6S)-3,4,5-triacetyloxy-6-sulfanyloxan-2-yl] methyl acetate, [propylamino-3-hydroxy-buta-1,4-dionyl]-isoleucylproline). The selected drugs and drug targets were obtained and prepared for molecular docking simulations. The molecular docking simulations were performed using AutoDockvina®-1.1.2 after validation of docking protocols while molecular dynamics simulations were performed with GROMACS-4.5.5. The binding energies were calculated using MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area). Tolmetin was predicted as potential antischistosomal drug with binding energies of -231.064 ± 18.550 and -338.636 ± 36.900 KJ/mol for sulfotransferase and thioredoxin glutathione reductase (TGR) respectively. Also diflunisal was predicted as potential antischistosomal drug with binding energies of -168.641 ± 20.370 and -290.117 ± 43.800 KJ/mol for sulfotransferase and TGR respectively. Non-covalent interactions and conformational changes were responsible for molecular recognitions and specificities and average bond measurement showed that carboxylic functional groups in diflunisal and tolmetin may interact covalently with -SH group of Cys159 in TGR. Confirmation of covalent interactions and in vitro validations are recommended.Communicated by Ramaswamy H. Sarma.

Recent Advances in the Synthesis of Antischistosomal Drugs and Agents.

Schistosomiasis is a notable neglected tropical disease caused by trematodes that infect mainly the intestines, bladder, and liver. Because of the unavailability of a schistosomiasis vaccine, control of the disease depends mainly on chemotherapy. Praziquantel (PZQ), which is active against all schistosome species (Among the five major species of human schistosomes-S. mansoni, S. haematobium, S. japonicum, S. intercalatum, and S. mekongi, S. mansoni is the most prevalent) as well as probably their hybrids and the recommended drug by the World Health Organization for schistosomiasis treatment at either the community or individual level, has become the exclusive drug because of its low cost and efficacy against the adult form of all schistosome species. In view of rapid re-infection following treatment and concern about the development of tolerance and/or resistance to praziquantel, there is an urgent need for research and development of novel drugs for the prevention and treatment of schistosomiasis. This comprehensive review shall attempt to briefly review the recent advances in the synthesis of antischistosomal drugs and agents in the literature from 1990s to now, particularly focusing on the context of potential development of antischistosomal agents. It shall be of interest for the pharmacologist.

Antischistosomal activity of a calcium channel antagonist on schistosomula and adult Schistosoma mansoni worms

Current schistosomiasis control strategies are largely based on chemotherapeutic agents and a limited number of drugs are available today. Praziquantel (PZQ) is the only drug currently used in schistosomiasis control programs. Unfortunately, this drug shows poor efficacy in patients during the earliest infection phases. The effects of PZQ appear to operate on the voltage-operated Ca2+channels, which are located on the external Schistosoma mansoni membrane. Because some Ca2+channels have dihydropyridine drug class (a class that includes nifedipine) sensitivity, an in vitro analysis using a calcium channel antagonist (clinically used for cardiovascular hypertension) was performed to determine the antischistosomal effects of nifedipine on schistosomula and adult worm cultures. Nifedipine demonstrated antischistosomal activity against schistosomula and significantly reduced viability at all of the concentrations used alone or in combination with PZQ. In contrast, PZQ did not show significant efficacy when used alone. Adult worms were also affected by nifedipine after a 24 h incubation and exhibited impaired motility, several lesions on the tegument and intense contractility. These data support the idea of Ca2+channels subunits as drug targets and favour alternative therapeutic schemes when drug resistance has been reported. In this paper, strong arguments encouraging drug research are presented, with a focus on exploring schistosomal Ca2+channels.

In vitro effect of current antimalarial drugs on the survival of paired Schistosoma mansoni adult worms and their egg production

Some field trials have already demonstrated the high antischistosomal potential of combination therapies using Artesunate (ART) and current antimalarial drugs (Boulanger <I>et al.,</I> 2007; Mohamed <I>et al.,</I> 2009; Sissoko <I>et al.,</I> 2009). The antischistosomal effects of these drugs are noteworthy, especially when they are used for the treatment of malaria in schistosomiasis endemic areas. However, the antischistosomal effects of Amodiaquine (AQ), Primaquine (PQ), Chloroquine (CQ) and Pyrimethamine (Py) have never been assessed by <I>in vitro</I> incubation. The objective of the present study is to assess the <I>in vitro</I> effects of current antimalarial drugs on the egg productivity of adult worm pairs of <I>S. mansoni</I> and their survival times. The effect of the current antimalarial drugs Mefloquine (MQ), quinine (QN), AQ, PQ, CQ, Sulfadiazine (Sf) and Py on the egg output of adult worm pairs of <I>Schistosoma mansoni</I> and their survival times during <I>in vitro</I> culture were assessed at a concentration of 10 Μg⁄ml. AQ, PQ, CQ and Py significantly inhibited the daily egg output of paired female worms at a concentration of 10 Μg⁄ml during the 1 or 2-day <I>in vitro</I> cultivation. However, QN and Sf did not significantly affect the daily egg output during the 8-day incubation. One-day exposure to MQ killed all paired male and female adult worms. AQ and PQ significantly decreased the survival of both paired male and female worms during the 14-day incubation, but QN, CQ, Py and Sf did not exert any similar effect. The present result is consistent with an assessment of the antischistosomal effects of artemisinin-based combination therapy in malaria and schistosomiasis co-endemic areas.

Antischistosomal therapy: Current status and recent developments.

Schistosomiasis remains one of the most prevalent parasitic infections in the world. Currently, Praziquantel (PZQ) is the drug being used to treat human schistosomiasis on a large scale. Millions of people are treated annually with praziquantel, and drug-resistant parasites thus are likely to evolve. This review focuses on current knowledge about the mechanisms of action of PZQ, possibility of PZQ resistance, potentially alternative drugs, and prospects for development of new schistosomicides .Vaccines production strategies represent an essential component for the future control of schistosomiasis as an adjunct to chemotherapy.