Schistosomiasis Drug Development: A Computational Approach

Review Article

J Drug Discov Develop and Deliv. 2023; 9(2): 1048.

Schistosomiasis Drug Development: A Computational Approach

Khwesa Peredy*

Material and Computational Chemistry, College of Natural and Computational Sciences, Addis Ababa University, Ethiopia

*Corresponding author: Khwesa Peredy Material and Computational Chemistry, College of Natural and Computational Sciences, Addis Ababa University, P.O. BOX 1176, Addis Ababa, Ethiopia. Email: [email protected]

Received: October 17, 2023 Accepted: November 20, 2023 Published: November 27, 2023


Schistosomiasis continues to be a significant global health concern, affecting millions of individuals worldwide. The limitations associated with the existing treatment, Praziquantel, highlight the urgent need for novel schistosomicides. The development of a structure-based drug with high efficacy offers a potential solution to the challenges posed by current treatments. Given the capital and time-intensive nature of traditional inhibitor identification methods, computational techniques have gained prominence as valuable tools in drug discovery. This study employed a comprehensive computational approach to identify potential drug candidates, laying the groundwork for future wet-lab experimentation.

In this research, in silico molecular docking analysis assessed the binding affinity of various compounds to the Schistosoma japonicum tegument protein 4 (SGTP4). To facilitate this analysis, homology modeling generated a reliable 3D structure of SGTP4. This rigorous approach, encompassing homology modeling and subsequent validation, ensured the reliability and high quality of the SGTP4 protein model, providing a solid foundation for subsequent molecular docking and drug discovery investigations. The ligands examined included Praziquantel , Licochalcone, P96, Licarin, and Harmonine. Ligand preparations were conducted using LigPrep within the Schrodinger Maestro suite, and pharmacokinetic parameters were evaluated using the QikProp tool within the Schrodinger-2019-4 software suite. Subsequently, AutoDockTools version 4 facilitated the docking analysis of the prepared ligands.

The docking results furnished valuable insights into the binding affinities and potential inhibitory activities of the assessed compounds against SGTP4. PZQ, Licochalcone, and P96 exhibited robust binding affinities and inhibitory potentials, characterized by their lower binding energies and Ki values. Licarin demonstrated moderate activity, whereas Harmonine exhibited comparatively weaker binding and inhibition.

The amalgamated results of docking analysis and ADMET simulations establish a foundation for the selection of lead compounds for further experimental evaluation in the quest for effective anti-schistosomal drugs. Among the evaluated compounds, Licochalcone and Licarin emerge as promising candidates, characterized by favorable molecular properties, drug-like attributes, and bioavailability. While PZQ retains its importance as a reference, its limitations underscore the necessity of exploring alternative compounds. Furthermore, P96 exhibits potential, particularly with structural modifications, warranting further investigation.

This study underscores the significance of computational methodologies in the initial stages of drug discovery. Nonetheless, it is essential to stress that wet-lab experimentation remains an indispensable step in drug development. The computational insights presented herein offer a compelling rationale for the wet-lab validation of the identified candidates. Such experiments can elucidate the mechanisms of action, evaluate safety profiles, and confirm efficacy against schistosomes. Therefore, we advocate for the integration of wet-lab experiments to complement computational approaches, presenting a synergistic strategy poised to address the deficiencies of PZQ and effectively combat schistosomiasis.

Keywords: Schistosomiasis, Drug discovery, Molecular docking, SGTP4 protein, Computational analysis, Neglected tropical disease


Schistosomiasis, an NTD, is a parasite illness transmitted by water and is prevalent in economically disadvantaged regions of Sub-Saharan Africa. According to multiple sources it is predicted that out of the global total of around 240 million cases of the disease reported in 2020, the majority, specifically 90% of the cases, were documented in the Sub-Saharan Africa region [1-3]. The disease's prevalence is impacted by the low socioeconomic position of the area, which is characterized by inadequate sanitation, weak health policies, and overall substandard living conditions [4]. In Africa, there is a prevalent reliance on herbal medications, with a significant proportion of the population, particularly in rural regions, relying on such remedies [5]. Hence, it is imperative to comprehend the utilization of traditional herbal remedies within these populations, considering the high incidence of schistosomiasis.

According to Gryseels et al. , the species that are considered to be the most clinically significant are S. mansoni, S. japonicum, and S. haematobium [6]. On the other hand, S. mekongi, S. guineensis, and S. intercalatum exhibit lower prevalence rates. The World Health Organization (WHO) reports that there is a global infection rate of roughly 229 million individuals, resulting in an estimated yearly mortality rate of over 200,000 [7]. Nevertheless, it is likely that this assessment is conservative, as the current diagnostic technologies exhibit limited sensitivity in detecting parasite infections of low intensity [8]. According to Kassebaum et al., this particular condition holds the second position in terms of both prevalence and socio-economic impact, with malaria being the only disease ranking higher [9]. Furthermore, it is responsible for a significant loss of over 2.6 million disability-adjusted life years (DALYs).

Human infection occurs when cercariae larvae, which are discharged by intermediate snail hosts, penetrate the skin upon exposure to freshwater that has been contaminated [10]. Subsequently, cercariae gain entry into the host's circulatory system and undergo maturation into juvenile and adult worms [11] the adult schistosomes, both female and male, are found in the blood vessels, where they engage in reproductive activities resulting in the production of eggs. These eggs are then expelled either by feces in the case of S. mansoni, S. japonicum, S. intercalatum, S. guineenses, and S. mekongi, or through urine in the case of infections caused by S. haematobium [12]. The presence of eggs in human tissues leads to the initiation of inflammatory immunological responses, characterized by the formation of granulomata. These immune reactions contribute to the impairment of organ function, giving rise to various diseases such as intestinal, hepatosplenic, or urogenital disorders [13] The eggs that are deposited into the environment undergo hatching in aquatic habitats, subsequently releasing the larval form known as miracidia. The Miracidia are responsible for infecting the intermediate hosts, so facilitating the continuation of the parasite's life-cycle.

The development of a vaccine for schistosomiasis has presented significant challenges [14]. As a result, the treatment and management of schistosomiasis still rely heavily on praziquantel , a medicine that has been in use for nearly 50 years [15]. Schistosomiasis is primarily prevalent in the Sub-Saharan African region, where the prevalence of infection is on the rise. This increase can be attributed to various factors, including climate change and socio-economic influences. Currently, praziquantel stands as the sole pharmaceutical agent available for the management of this incapacitating ailment. Praziquantel exhibits several advantageous properties:The treatment exhibits efficacy against several species of Schistosomes; It is characterized by its affordability and easy accessibility; Furthermore, it demonstrates a favorable safety profile, being well-tolerated across all age groups of patients. Regrettably, the utilization of Praziquantel is constrained by the subsequent factors: There are several challenges associated with the use of praziquantel for the treatment of schistosomiasis. Firstly, drug resistance has been observed, which reduces the effectiveness of the medication. Secondly, there is a lack of patient compliance to treatment, particularly in certain populations. This non-adherence to the prescribed regimen can hinder the successful management of the disease. Additionally, praziquantel is ineffective against immature forms of the Schistosoma species, limiting its efficacy in treating infections at early stages. Lastly, it is important to note that praziquantel does not provide protection against re-infection of schistosomiasis, necessitating additional preventive measures. Moreover, there has been a rise in the phenomenon of parasite change and modification, leading to an escalation in the global parasite burden and the occurrence of co-infection with many strains of Schistosoma parasites [15-17]. In conjunction with instances of cerebral schistosomiasis in various regions worldwide, there exists a pressing necessity for an alternative pharmaceutical compound with anti-schistosomal properties or for enhancing the effectiveness of Praziquantel administration through methods such as nanotechnology, in order to attain targeted therapeutic outcomes against schistosomiasis, particularly within the Central Nervous System.

Praziquantel is widely recognized for its efficacy in targeting both adult and schistosomula stages across several types of schistosomes. In addition, it should be noted that PZQ is often supplied in a racemic mixture, meaning that only one of the two stereoisomers (namely, the R-PZQ stereoisomer) is pharmacologically active. In addition to its pharmacological inactivity, the S-PZQ compound is implicated in the bitter taste and the substantial dimensions of PQZ tablets. These characteristics have been seen to diminish patient adherence and render the medication unsuitable for pediatric use [18]. Furthermore, the utilization of PZQ in large-scale drug administration initiatives over an extended period of time has the potential to provide a selective pressure that could facilitate the emergence of resistance in parasites [19]. Indeed, studies have shown a decrease in the effectiveness of praziquantel in both laboratory and field isolates [20,21].

Since its initial clinical studies in the late 1970s, Praziquantel has demonstrated both safety and efficacy against all three primary manifestations of the disease. Furthermore, the ongoing reduction in costs has rendered this medication more accessible, with a current price range of approximately 7-19 US cents per 600 mg tablet [22]. According to [23], administering a solitary oral dosage ranging from 40 to 60 mg/kg is effective in attaining cure rates between 60% and 90% [23]. This approach is particularly advantageous in promoting adherence among patients, particularly children. Despite sporadic and isolated incidents reported by Botros et al., the occurrence of clinically significant and widespread resistance has not yet been observed [24]. The fortuitous circumstance described herein presents a notable juxtaposition to the circumstances surrounding certain other Neglected Tropical Diseases (NTDs) as documented by [25]. These NTDs necessitate the administration of outdated and frequently toxic medications via parenteral routes, requiring several days or weeks of treatment. Moreover, these diseases are progressively encountering challenges related to drug resistance, as indicated by Pink et al. [26].

However, the utilization of a solitary pharmaceutical agent for addressing the healthcare needs of a populace exceeding 200 million individuals who are infected, as well as an additional 700 million individuals who are at risk throughout three continents [1,27], appears notably precarious when contemplating the potential emergence of drug resistance. Moreover, it should be noted that PZQ is not exempt from certain challenges or drawbacks. One of the primary limitations of PZQ is its limited efficacy against migratory juvenile and sub-adult worms, as noted by [28]. Consequently, in order to achieve successful therapy and sustainable control, it is necessary to administer PZQ regularly. Recent scholarly discourse on the treatment landscape of human helminthiases has placed emphasis on the renewed exploration of alternate options to praziquantel , as highlighted by [29]. This includes the investigation of pharmacological combinations that involve the incorporation of PZQ, as discussed by [15].

The second choice offers the longer-term advantage of increasing PZQ availability while delaying the establishment of resistance to this most priceless of medicines, even if it is more challenging and expensive to create. In researching anti-schistosomal drugs (and anthelmintics in general), our knowledge of the molecular drug target or mechanism of action has been rather constrained. The suppression of redox and proteolytic enzymes [30] and heme aggregation [31] are two major breakthroughs in this field.

Contrasting sharply with the vast array of validated targets that serve as the cornerstone of drug development initiatives by Public-Private Partnerships (PPPs) addressing other globally significant infectious illnesses like malaria and the trypanosomiases is the paucity of established molecular therapeutic targets for this parasite. The recently published draft genomes of Schistosoma mansoni [32] and S. japonicum, as well as the initial efforts to prioritize these targets [15]; TDR Drug Targets Prioritization Database), may help to more effectively address the limited number of targets. Phenotypic screening, a method often used in the discovery of schistosome drugs, includes evaluating a compound's activity in vitro using whole organism experiments, usually using adult worms. Additionally, to evaluate the efficacy of these substances, animal models of illness are often used [33].

The majority of the time, these tactics are used without having a thorough understanding of the target or the action's process. It's also possible that they are methods whose bioactivity has already been confirmed in related parasitological or biomedical situations [34]. These organizations have shown their value. For instance, PZQ underwent testing in an animal model of schistosomiasis after being first developed as a veterinary cestocide [35]. Evidence about its mode of action was subsequently gathered. However, because these methodologies heavily rely on a small number of talented research teams with the necessary skills for managing the complex life cycle of schistosomes and dealing with only small numbers of the parasite, the rate of advancement using these approaches is relatively slow.

An Examination of Historical and Contemporary Therapeutic Approaches for Schistosomiasis

The proposed therapeutic option to eradicate schistosomiasis in 1984 was chemotherapy, as suggested by the WHO Expert Committee [35]. Chemotherapy remains the exclusive approach for the management of schistosomiasis, relying exclusively on a monotherapy regimen using a single dosage of Praziquantel.

Among the several pharmacological medicines that have been studied, praziquantel has emerged as the main anti-schistosomal drug. The pathogenic disease known as schistosomiasis is caused by the Schistosoma species, and praziquantel is effective against all known Schistosoma species. The treatments may lessen the severity of symptoms and reduce the burden that parasites create. of addition, this medication is well-liked for its simplicity of use, potency, and affordability.

Although the specific method for treating schistosomiasis is still not fully understood, one often proposed mechanism is the rapid remodeling of the muscles in the parasite worms [36,37]. Provided evidence of the phenomena mentioned above. These researchers saw that the worm's muscles changed and contracted as a consequence, which was probably caused by the quick input of calcium ions into the schistosome. A notable research by [37], which focused on the voltage-gated calcium channels present in schistosomes as a potential target for PZQ, provided evidence for the aforementioned assertion. The study's authors suggested that the observed effect of PZQ on the control of Ca2+ levels in schistosomes is consistent with the mechanism through which PZQ functions. It was discovered that the particular structural traits of -subunits found in schistosome channels vary from those of conventional -subunits seen in other situations. It has been shown that these distinct -subunits block the passage of current via the schistosome channels' 1 subunit, with which they are intricately linked.

A second hypothesis put out by the research was that PZQ contributed to the enhancement of channel availability for current conduction, interfering with the interaction between the 1 and subunits in these channels. As a result, this alteration affected the way intracellular calcium levels were regulated [37].The tegument of schistosomes has also been shown to undergo morphological alterations, according to studies. The early observations of surface blebbing and vacuole growth inside the tegument were made by [23,38]. An enhanced presentation of antigens on the parasite's surface is the outcome of the morphological changes mentioned in the research by [39]. According to [39], PZQ's lipophilic character, which makes it easier for it to interact with the hydrophobic cores of the tegument, is the method by which it affects the exposed antigens.

Trematodes have a poor digestive system, yet Schistosoma species may survive long periods of in vitro incubation without depending on gastrointestinal food absorption [40,41]. In the early stages of the trematode's life cycle, when the gut is still developing, glucose absorption in trematodes is shown [42]. The primary source of energy for both juvenile and adult schistosomes is plasma glucose acquired from the host. According to physiological investigations [42,43], a process mediated by carriers facilitates the entrance of glucose into the tegument.

The Schistosome Tegument: Exploring Potential Molecular Targets

There are several targets on the tegument's surface. To effectively target the male schistosomes' tegument surface, engineered drug-loaded nanoparticles need to contain Acetylcholinesterase (AChE), Schistosoma Japonicum Tegument Protein 1 (SGTP1), Schistosoma Japonicum Tegument Protein 4 (SGTP4), and a nicotinic type of acetylcholine receptor (nAChR). Among other components, dynein, aquaporins, and tetraspanins are additional significant surface proteins found on the tegument that may be targeted. The substances found on the tegument's surface are essential because they serve as the main molecular targets for the development of novel therapeutic compounds and vaccines that target the Schistosoma parasite.

Potential molecular targets for nano-delivery systems in glucose transporters

Numerous studies [44-46] have shown that the availability of energy in the form of glucose is necessary for the survivability of Schistosoma parasites. The primary site of energy (glucose) consumption is the tegument, not the intestinal cecum. According to [44], the presence of glucose transporters on the tegument facilitates the process of absorption. In their work, [44] they found and examined three distinct cDNAs. The protein sequences of these cDNAs were found to be structurally and logically similar to those of facilitated diffusion transporters found in mammals, microbes, and plants. Two distinct glucose transporters, SGTP1 and SGTP4, were identified in the tegument.

The study also found that the SGTP 1 and 4 genes are expressed in adult and larval schistosomes of both sexes, enabling efficient glucose uptake from the host organism. Only two of the four encoded glucose transporters found in Schistosoma mansoni's genome, according to [47], were shown to help in glucose diffusion. Their research's findings also showed that Schistosoma mansoni's class 1 glucose transporters were unable to facilitate glucose transfer, and that this function originated independently in the schistosome-specific glucose transporter.

The glucose transport routes of schistosome platyhelminthes-specific transporters and those found in humans were significantly different, according to. The sequences of SGTP1 and 4 share 60% of the same letters, according to earlier studies. In their investigation, [47] employed electron microscopy techniques to spatially locate the different locations of these transporters on the tegument. The scientists observed that SGTP1 was mostly present in the basal lamina, with a secondary and less significant presence beneath the muscle cells. Unbound glucose may be more likely to cross the epidermis and enter the fluids around the parasite's internal organs as a result of this process. According to [47], SGTP4 was shown to be evenly distributed throughout the dorsal and ventral surfaces of both male and female teguments, each of which had a distinctive double lipid bilayer structure. According to [44,45], SGTP4 is thought to have a role in the transfer of glucose from the host circulation into the parasite tegument due to its specific localization on the outer tegumental membrane.

Additionally, the transformation of free-living cercariae into schistosomula is mediated by SGTP4. The host satisfies the parasite's need for high glucose absorption during both the schistosomula stage and maturity, as shown by [44,45]. As a consequence, [46] findings support the idea that SGTP proteins might be used in nano-delivery systems. In their research, the overexpression of the SGTP4 and SGTP1 genes was reduced in the schistosomula and adult worm life stages via RNA interference (RNAi). The purpose of the present investigation was to assess how important these proteins were to the parasite. The ability of glucose to be transported was diminished when SGTP4 or SGTP1 were downregulated in comparison to the control. The study also discovered that, in comparison to downregulating just one SGTP gene, downregulating both SGTP1 and SGTP4 at the same time lowered the parasite's capacity to aid glucose transport. Furthermore, there were no obvious phenotypic differences between the suppressed parasites and the control group after an extended period of incubation on a nutrient-rich medium.

The role of SGTP1 and SGTP4 in facilitating the transfer of exogenous glucose from the mammalian host, which contributes to the parasite's regular development, was lastly hypothesized to be crucial. The aforementioned finding was made as a consequence of an empirical analysis of parasites with reduced SGTPs, which significantly reduced their ability to survive within infected experimental animals [46,48]. Found that the Akt/Protein kinase B signaling pathway controls glucose absorption in Schistosoma mansoni, which provided evidence in favor of the aforementioned theory. The study found that the host's natural amino acid, L-arginine, may activate Akt. In addition, it has been shown that insulin effectively raises Akt signaling in both adult and schistosomula teguments. During host invasion, the upregulation and maturation of SGTP4 on the surface of the parasite's larval stage were reduced due to the downregulation of Akt. In mature worms, the observed inhibition of SGTP4 overexpression in the tegument was associated with a reduction in glucose uptake.

Therefore, a more potent alternative to current anti-schistosomal therapy may be achieved by conjugating nanoparticles with specific agents such as antibodies, aptamers, antibody-like ligands, peptides, and small molecules with great selectivity for SGTP proteins. This plan would enable the targeted delivery of anti-schistosomal medications via nanotechnology. The development of nanoparticulate systems made possible by nanotechnology has enabled scientists to produce nanocarriers with the necessary selectivity for medication delivery. These nanocarriers may include pharmaceuticals, increasing their efficacy and enabling more precise delivery. Overexpressed receptor molecules, particularly SGTP proteins, which act as binding sites for possible therapeutic medications, are to blame for the behavior that has been seen. It is theoretically possible to enhance the localization of therapeutic medications within certain organs and tissues by modifying drug-containing nano-delivery systems with ligands that target specific receptors. Therefore, a promising method for the creation, development, and administration of anti-schistosomal drugs is the use of nano-delivery systems with ligands specific for Schistosoma Granulocyte Transmembrane Proteins (SGTPs) as receptors.

It's crucial to comprehend the Praziquantel drug's mechanism of action while looking for novel schistosomiasis chemotherapy treatment options. The underlying mechanism of PZQ has been the subject of a great deal of study and examination. A PZQ binding site was discovered by [49] in the voltage sensor-like region of a schistosome transient receptor potential melastatin ion channel (Sm.TRPMPZQ) using ligand- and target-based approaches. This binding site was located in a juxtamembrane cavity. The authors demonstrated that PZQ may open the Sm.TRPMPZQ channel, causing calcium to influx and the paralysis of the parasitic flatworm. Le Clec'h et al. also demonstrated that the transient receptor potential channel in S. mansoni had a role in PZQ response variation by using genome-wide association to pinpoint the loci responsible for PZQ response variance. [50] Suggested that nanomolar concentrations of PZQ might activate this channel. The Park group created 43 praziquantel derivatives, including the enantiomers (R)-PZQ, (S)-PZQ, and the primary trans-(R)-4-OH PZQ metabolite, in order to investigate the pharmacological specificity of the schistosome TRP channel produced by PZQ.

The cyclohexyl moiety (R group, as depicted in Figure 1A) in PZQ is essential to its efficacy, according to research into the structure-activity connections of these analogs. Analogs with diminished activity or potency were produced by significant changes to this molecule [49]. The findings were in line with other studies suggesting a potential connection between the cyclohexyl group's structural characteristics and its antitischistosomal activities [5]. PZQ undergoes fast metabolism, which leads to the production of a substantial trans-cyclohexanol metabolite, as identified by [51]. However, it was discovered that this metabolite was much less efficient than PZQ. Trans-cyclohexanol metabolite ketone oxidation products, as well as other analogues, were produced by [52] and had increased metabolic stability. The action of these substances against young S. japonicum and S. mansoni is minimal to moderate.