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Innovative Medicines & Omics Femtomolar inhibition of pseudoeriocitrin

2.5. Absorption, distribution, metabolism, and that cyclic side chain residues, such as PHE131 and
excretion (ADME) prediction PHE134, contribute to hydrogen bond formation rather
SwissADME web server was used to estimate the ADME than aromatic interactions. Five hydrogen bonds were
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properties of pseudoeriocitrin and eriocitrin. Their predicted through Biovia 2020 Client (as indicated by the
ability to cross the blood-brain barrier, gastrointestinal green dashed lines in Figure 2B).
absorption, and oral bioavailability were evaluated through One of the most important factors in the interactions of
chemical computation. pseudoeriocitrin is the chemical attraction arising from the
The SwissADME website provides users with free and oxygen atoms on each ring of the ligand. As illustrated in
reliable prediction models for various properties, including Figure 2B, residues LEU599, GLY600, PHE134, PHE131,
physicochemical characteristics, pharmacokinetics, SER588, and TYR486 formed hydrogen bonds with the
drug similarity, and medicinal chemistry relevance. oxygen atoms on the ligand. Specifically, PHE134 formed
These models incorporate well-established methods two hydrogen bonds with the oxygen atoms of the ligand,
such as BOILED-Egg, iLOGP, and Bioavailability Radar. one at a distance of 2.75 Å and the other at 3.29 Å, while
Lipophilicity, molecular size, polarity, solubility, flexibility, SER588 formed a hydrogen bond at a distance of 1.81 Å. In
and saturation properties are used to generate a radar addition, PHE602 formed an aromatic interaction with one
plot. These properties are the fundamental criteria to of the two rings in the center of the ligand and an amide-π
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determine whether the predicted physicochemical and interaction with the other ring. PRO and ALA residues
pharmacokinetic values of a bioavailable compound fall also formed π-alkyl interactions with two different rings
within reasonable limits. of the ligand. Notably, each ring of the ligand had at least
one π–alkyl interaction.
According to the bioavailability radar, a bioavailable
compound should meet the following criteria: molecular The hydrophobicity of the region formed by the
weight between 150 and 200 g/mol, topological polar residues surrounding pseudoeriocitrin is crucial because
surface area between 20 and 130 Å , lipophilicity it directly affects the interactions of the ligand. Figure 3
2
(XLOGP3) between −0.7 and +5.0, carbon fraction in sp illustrates the hydrophobic and hydrophilic regions
3
hybridization (a saturation marker) >0.25, solubility (logS) around pseudoeriocitrin in the binding site of rat CPT 2.
<6, water solubility score falls between 1 and 3 (on a The presence of polar residues outside the hydrophobic
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scale of 1 – 5, with 1 indicating the highest solubility and surface, particularly the side chains of amino acids, such
5 indicating the lowest solubility), and number of rotatable as alanine, valine, glycine, phenylalanine, and leucine,
bonds between 0 and 9. 27 created hydrophilic areas adjacent to the apolar residues
that border one side of the ligand. For comparison, the
3. Results interactions between eriocitrin and the residues of rat

3.1. Evaluation of potential interactions between CPT 2 are illustrated in Figure 4. In this case, a different
pseudoeriocitrin and rat carnitine palmitoyl structure of CPT 2 was used (PDB ID: 2FW3), which
transferase 2 is distinct from the CPT 2 (PDB ID: 2H4T) used in
Figures 2 and 3. Meanwhile, Figure 5 depicts the varying
One of the findings of this study was that the K of potential interactions between pseudoeriocitrin and the
i
pseudoeriocitrin against rat CPT 2 (PDB ID: 2H4T) was residues of rat CPT 2 (PDB ID: 2FW3). Video A1 illustrates
15.83 fM. This result suggests that pseudoeriocitrin may the localization of pseudoeriocitrin in the enzyme CPT
act as a highly potent CPT 2 inhibitor. However, it should 2 (PDB ID: 2FW3). The surface of the CPT 2 (PDB ID:
be noted that pseudoeriocitrin is a virtual molecule and 2FW3) enzyme and the potential ligand entry site are
is not accessible in existing databases. Therefore, it can demonstrated in Figure 6A, while Figure 6B displays the
only serve as a reference for the design of de novo drug position of pseudoeriocitrin after it has entered the CPT
candidate molecules. 2 enzyme.
Studies on the potential interactions between
pseudoeriocitrin and the rat CPT 2 enzyme (PDB ID: 3.2. Evaluation and comparison of potential
2H4T) revealed a significant number of interactions interactions between pseudoeriocitrin and AsFR or
with the residues, as illustrated in Figure 2A. While most hFR
of these residues were apolar amino acids, the polar Pseudoeriocitrin exhibits a strong binding affinity
hydrophilic residues such as serine and tyrosine (TYR486) to AsFR, with a K value of 512 pM, making it highly
i
were located in close proximity to pseudoeriocitrin, effective in inhibiting this enzyme. The positions of
forming aromatic interactions. Figure 2B demonstrates pseudoeriocitrin on AsFR and hFR enzymes are illustrated

Volume 2 Issue 2 (2025) 85 doi: 10.36922/imo.6026