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Innovative Medicines & Omics Femtomolar inhibition of pseudoeriocitrin

worldwide were infected with Enterobius vermicularis in A B
2015. 3
β-tubulin, carnitine o-palmitoyltransferase-2 (CPT 2),
and fumarate reductase have recently been the primary
antinematodal targets for the development of several
anthelmintics, such as albendazole, mebendazole,
ivermectin, and thiabendazole. Due to the unknown
genome sequence and the lack of crystallized structure of Figure 1. Molecular representation of eriocitrin and pseudoeriocitrin.
Syphacia obvelata-derived proteins, the homology modeling (A) Molecular structure showing the rings forming eriocitrin. The bond
of mitochondrial cytochrome c oxidase (COX) proteins can leading to the formation of pseudoeriocitrin is formed between the
chromene-4-one ring and the oxygen atom of the hydroxyl group of the
be useful in in silico docking experiments to investigate the chromene-bonded monosaccharide of O-β-rutinoside. (B) Molecular
antinematodal properties of certain drug candidates against representation of pseudoeriocitrin.
S. obvelata. Performing protein-ligand docking simulations
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using in silico molecular modeling is the initial step in This study aimed to explore the structure and
developing new drugs. These computational experiments interactions of pseudoeriocitrin, potentially related to its
could provide researchers with atomic-level information anthelmintic activity. An in silico docking study provides
on the interactions between drug molecules and target insights into inhibition potency, serving as a foundation
proteins. Such experiments are highly valuable in reducing for new drug synthesis research. In addition, these in silico
the workload involved in drug development. 5 results may assist drug designers interested in the structure-

Eriocitrin, (2S)-2-(3,4-dihydroxyphenyl)-5-hydroxy-7- activity relationship of highly potent multi-inhibitors.
[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)- This study is the first to report a virtual molecule with
3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl] femtomolar K against multiple proteins. Consequently, its
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oxan-2-yl]oxy-2,3-dihydrochromen-4-one, is an interactions with anthelmintic target proteins, researched
eriodictyol-derived flavonoid glycoside mainly found in through in silico methods, provide novel and original
lemon peel, citrus pulp, and certain plants, such as thyme data. Furthermore, this study is the first to elucidate the
and mint. It is formed by the addition of O-β-rutinose at the structure-activity relationship of a multi-radical virtual
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7 position of eriodictyol. Eriocitrin exhibits antioxidant, molecule capable of multi-inhibition at exceptionally low
th
anti-inflammatory, and antiproliferative properties. The K values.
7-9
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study by Ferreira et al. reported the presence of eriocitrin 2. Materials and methods
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and its metabolites in various organs and body fluids of
rats administered with orange peel extract. The major 2.1. Acquisition and preparation of pseudoeriocitrin
metabolites of eriocitrin are homoeriodictyol and homo- Pseudoeriocitrin was retrieved from the FooDB database
eriodictyol-7-O-glucuronide (hERD-7-O-Gluc). The half- (www.foodb.ca) as a PDB file in November 2019 (ligand
life of these metabolites in blood plasma is 3 – 3.2 h. In ID: FDB016547). In the PDB file, deposited as eriocitrin
addition, hesperetin-7-O- and hesperetin-3’-O-gluconic in the FooDB database, all Z coordinates were set to 0.
acid, metabolites of eriocitrin, were detected in both tissue This PDB file was converted to a PDBQT file using the
and urine samples of the rats. The concentration of hERD- AutoDock Tool (ADT). 11,12 When the Z coordinates were
7-O-Gluc reached approximately 8 ng/g in blood plasma 0, the ADT program ignored the hydrogen atoms in the
10 h after administration, while that of hERD-4’-O-Gluc hydroxyl groups and assumed an additional bond in the
peaked at approximately 2 ng/g after 6 h, representing core structure. This assumption was based on the sufficient
the highest concentration in the blood. However, distance between the C8 atom in the chromene ring of the
gastrointestinal absorption of eriocitrin was found to be ligand and the oxygen atom of the hydroxyl group at the
extremely low, with a total bioavailability of <1%. C3 position of the rutinoside group, which allowed for
In our previous in silico computational study, we potential bonding (Figure 1). As a result, the generated
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investigated the anthelminthic effect of eriocitrin, whose PDBQT file lacked hydrogen donors. The 3D molecular
molecular structure is shown in Figure 1A. Interestingly, representation of pseudoeriocitrin is shown in Figure 1B.
we found an additional bond in eriocitrin when studying
its possible interactions with target proteins. Further 2.2. Preparation of proteins
analyses of the eriocitrin derivative in the present study Proteins and enzymes in nematodes that could serve as
found that pseudoeriocitrin inhibits several proteins at the potential drug targets were chosen. Biovia Discovery
femtomolar level (inhibition constant, K = 10 mol/L). Studio 2020 Client and ADT software were used for
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Volume 2 Issue 2 (2025) 83 doi: 10.36922/imo.6026