The selected compounds from S. natalensis bulb were carefully modeled using ChemDraw Ultra 12.0.2 software and saved as MDL SDfile (*.sdf) format (Table 1). The modeled structures were subjected to Spartan’14 software to view a 3D version of the modeled structures and then optimized via energy minimization. The minimization of the studied molecular compounds was executed using Molecular Mechanics Force Field, while the optimization of the compounds was accomplished using density functional theory (DFT) and 6-31G* was used as basis set. The optimized compounds were saved and the calculated descriptors for each molecule were reported (Oyeneyin et al., 2022; Wang et al., 2020).

Table 1.
Two-dimensional (2D) structure of the studied compound.

Elaborated by the authors using data from Sparg et al., (2002).

Two targets (glutathione S-transferase [PDB ID: 1gtb]) (McTigue et al., 1995) and thioredoxin-glutathione reductase (PDB ID: 3h4k) (Angelucci et al., 2009) were retrieved from protein data bank (Fig. 1a and b). The two receptors were subjected to Pymol software where suitable implements were deployed to treat and prepare glutathione S-transferase (PDB ID: 1gtb) and thioredoxin-glutathione reductase (PDB ID: 3h4k) for docking. The amino acids present in each of the downloaded receptor were carefully checked and any other materials (i.e., crystallographic water and small molecules rooted in each of the receptor) different from amino acids were deleted and saved in *.pdb format. Also, all the possible missing amino acids in each clean receptor were replaced using Swiss Pdbviewer 4.1.0 version and saved in *.pdb format before identification of the binding site in each receptor using Autodock tool software. The center and size in X, Y and Z directions which show the located binding site for glutathione S-transferase (PDB ID: 1gtb) were 11.97, 45.043 and 32.999 for the center and 50, 52 and 60 for size; and for thioredoxin-glutathione reductase (PDB ID: 3h4k) were 45.78, –0.593 and 16.04 for the center and 80, 90 and 78 for size. The calculation of binding affinity for the studied complex was executed via Autodock vina software and the discovery studio was used to view the interaction between the ligands and the receptors.

Figure 1.
Tree-dimensional (3D) structures of transferase and reductase enzymes: (a) 3D structure of glutathione S-transferase and (b) 3D structure of thioredoxin-glutathione reductase.

The study of pharmacokinetics plays a crucial role in drug design and discovery since only chemical compounds with worthy drug-likeness features, as well as outstanding absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles move into the advance stage of drug production (Lawal et al., 2021). Therefore, 5-[(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxy-1,2,3,6,7,8,9,11,12,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl]pyran-2-one (9) with lower binding affinity value, which indicate better inhibitory activities, was reconnoitered for ADMET study via ADMETlab (https://admetmesh.scbdd.com/), an online ADMET software.

One of the crucial descriptors calculated from optimized molecular compounds as described by many researchers are the highest occupied molecular orbital energy (E_HOMO), and lowest unoccupied molecular orbital energy (E_LUMO) (HOMO-LUMO energies). The part taken in overriding vast array of chemical and biological interactions by HOMO-LUMO energies cannot be easily neglected (Saranya et al., 2018). The E_HOMO indicates molecule with greater strength to donate electron while E_LUMO indicate molecules with greater strength to accept electron from neighboring compounds. In this work, we observed that (3R)-5,7-dihydroxyspiro[2H-chromene-3,4’-9,11-dioxatricyclo[6.3.0.0^3,6]undeca-1(8),2,6-triene]-4-one (3) has highest strength to donate and receive electrons from nearby compounds. Also, lower band gap indicates spontaneous interactions between two molecules (Latona et al. 2022a); thus, (3R)-5,7-dihydroxyspiro[2H-chromene-3,4’9,11-dioxatricyclo[6.3.0.0^3,6]undeca-1(8),2,6-triene]-4-one (3) showed a greater strength to interact with neighboring compounds than other studied compounds (Supplementary Material 1). As we observed in this work, lower number of atoms highly contributed to high level of interacting ability of compound 3; this revealed the effectiveness of the combination of the atom as well as the bonds present in (3R)-5,7-dihydroxyspiro[2.-chromene-3,4'-9,11-dioxatricyclo[6.3.0.0^3,6]undeca-1(8),2,6-triene]-4-one (3). Other descriptors obtained from compounds from S. natalensis bulb were also reported in Table 2.

Table 2.
The selected descriptors obtained from compounds from S. natalensis bulb.

The assessment of the orientation of the selected compounds from S. natalensis bulb in the active site of the targets glutathione S-transferase (PDB ID: 1gtb) and thioredoxin-glutathione reductase (PDB ID: 3h4k) were carefully studied using docking method. The biochemical and biological connections between the studied complexes were exposed as well as the calculated binding affinity for the studied complexes were thoroughly investigated and reported. Adeoye et al. (2022) reported that biochemical and biological capability of any compound may and may not reveal its inhibition capacity. The inhibition capacity of any compound against the target is a function of the type of nonbonding interactions that occur between such complexes (Latona et al., 2022b). Therefore, 5-[(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxy-1,2,3,6,7,8,9,11,12,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl]pyran-2-one (compound 9) with –34.3 kJ mol^–1 (PDB ID: 1gtb) and –39.3 kJ mol^–1 (PDB ID: 3h4k) possessed greater tendency to inhibit glutathione S-transferase and thioredoxin-glutathione reductase than other studied compounds (Figs. 2 and 3). The calculated binding affinities for compound 1–10 against glutathione S-transferase (PDB ID: 1gtb) were –29.7, –29.3, –31.0, –31.4, –31.8, –33.5, –30.5, –34.3, –34.3, and –31.4 kJ mol^–1, respectively. This showed that all the compounds, except compounds 1, 2 and 7, could be good inhibitors for glutathione S-transferase as compared to Praziquantel. Also, docking results of optimized compounds 1–10 against thioredoxin-glutathione reductase (PDB ID: 3h4k) were –31.8, –32.2, –34.3, –33.9, –34.3, –33.5, –32.6, –34.7, –39.3, and –36.8 kJ mol^–1, respectively, indicating that all the phytochemicals could serve as inhibitors for thioredoxin-glutathione reductase (Table 3). According to Olasupo et al. (2021), the lower the binding affinity value of a compound, the better the ability of the compound to inhibit the target; hence, compound 9 has outstanding binding affinity and a greater tendency to inhibit glutathione S-transferase and thioredoxin-glutathione reductase, thereby hindering the activities of schistosomiasis. Also, this work agreed well with the work carried out by El-Seedi et al. (2012), which authenticated the biological activity of Asparagaceae as antischistosomiasis. Similar results were reported by Akachukwu et al., (2017) when 27 bioactive compounds of some medicinal plants were screened against Schistosoma cell lines (PDB ID: 1M9A and 2X99). The docking results revealed that quercetin-(3`-O 4```)-3``-O-methyl kaempferol and quercetin presented binding energies of –39.41 and –38.99 kJ mol<sup>–1</sup> against 1M9A cell lines of Schistosoma, respectively. Also, the binding affinities calculated for β-solamarine, solamargine and quercetin-(3`-O 4```)-3``-O-methyl kaempferol against 2X99 cell lines of Schistosoma were –38.99, –38.58 and –39.41 kJ mol^–1, respectively (Akachukwu et al., 2017). This was similar to binding energy calculated for 5-[(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxy-1,2,3,6,7,8,9,11,12,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl]pyran-2-one (9) against thioredoxin-glutathione reductase (PDB ID: 3H4K). This was higher than binding affinities reported by Mtemeli et al. (2022) from docking Cucurbita maxima against Schistosoma mansoni purine nucleoside phosphorylase (SmPNP) and Schistosoma haematobium 28-kDa glutathione S-transferase (Sh28kDaGST). The results showed that binding affinities of the most promising compounds, momordicoside I aglycone and balsaminoside B were –33.1 and –32.2 kJ mol^–1 with SmPNP and Sh28kDaGST, respectively.

Figure 2.
Biochemical interaction between Compound 9 and glutathione S-transferase.

Figure 3.
Biochemical interaction between Compound 9 and thioredoxin-glutathione reductase.

Table 3.
Calculated binding affinity and residues involved in the interactions.

Moreover, the work carried out by El-Seedi et al. (2012) on Asparagus stipularis Forssk., which was commonly known in Egypt as agool gabal, revealed the efficacy of medicinal plant as antischistosomiasis. The extracted asparagalin A was observed to be effective against schistosomiasis. This was confirmed through the efficiency of the studied compound (asparagalin A) against worm egg-laying capacity of S. mansoni thereby down-regulating the activity of schistosomiasis (El-Seedi et al., 2012) and this correlated with the inhibiting activity of the studied S. natalensis bulbs.

More so, the inhibiting capacity of three medicinal plants (Artemisia annua, Nigella sativa, and Allium sativum) explored by Fadladdin et al. (2022) against S. mansoni adult worms was experimentally studied. The concentration of 500 m/dm3, 250 m/dm3, and 125 m/dm3 of A. annua proved to be more effective against adult worms when compared to similar concentration of N. sativa, and A. sativum against the adult worms. Greater morphological changes were observed in the activity of A. annua on S. mansoni adult worms; however, lesser morphological changes were shown in the activities of N. sativa, and A. sativum on the S. mansoni adult worms. This inhibiting activity of A. annua on S. mansoni agreed with efficiency of S. natalensis bulbs as antischistosomiasis due to greater ability to hinder the activity of S. mansoni than praziquantel (reference drug) (Fadladdin et al., 2022).

The ADMET properties for compounds . and praziquantel (referenced drug) were accomplished using ADMETlab software and series of factors were considered such as physicochemical property, medicinal chemistry, absorption, distribution, metabolism, excretion, toxicity, environmental toxicity, tox21 pathway, toxicophore rules. The calculated molecular weight for compound . fell within the acceptable range of 100–600 amu and this was confirmed to help it physicochemical property. Also, number of hydrogen bond acceptors (0–12), number of hydrogen bond donors (0–7), number of rotatable bonds (0–11), number of rings (0–6), number of atoms in the biggest ring (0–18), number of heteroatoms (1–15), formal charge (–4 to 4), topological polar surface area (0–140) for compound . were within the acceptable range and its ability to act as potential drug proved to be valid (Supplementary Material 2 and 3).

As shown in Supplementary Material 2 and 3, synthetic accessibility score (SAscore) for compound 9 (5.052) was within the acceptable range for ease of synthesis of drug-like molecules (< 6) and this showed that compound 9 can easily be synthesized. Also, compound 9 obeyed Lipinski rule of five and other factors considered were reported in Supplementary Material 2 and 3. More so, the ADMET properties for compound 9 were in line with the ADMET properties obtained for the referenced drug (praziquantel).

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