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Gene & Protein in Disease In silico insights on fisetin’s antidepressant effects

Table 1. Physicochemical, pharmacokinetics, and potential, positive regulation of neuron death, chemical
drug‑likeness properties of FT synaptic transmission post-synaptic, and regulation of
neurotransmitter levels (Figure 3A). MF analysis showed
PubChemID 5281614 163 items, with the top five items being G protein-coupled
Mol ID MOL013179 adenosine receptor activity, cholinesterase activity,
Molecule Name Fisetin sphingolipid floppase activity, monoamine oxidase
Formula C15H10O6 activity, and tau-protein kinase activity (Figure 3B). The
OB (%) 52.6 CC analysis identified 103 items, with the leading five
BBB −0.69 being the protein kinase 5 complex, post-synaptic density,
DL 0.24 axon, dendrite, and axolemma (Figure 3C). The results
MW (g/mol) 286.24 of the KEGG enrichment analysis detected a total of 101
signaling pathways with a significance level of P < 0.05,
Hacc 6 among which the 10 most important pathways were as
Hdon 4 follows: pathways in cancer, bladder cancer, diabetic
Rbon 1 cardiomyopathy, cocaine addiction, drug metabolism,
TPSA (Å) 111.13 endocrine resistance, neuroactive ligand-receptor
Lipinski Yes interaction, interleukin (IL)-17 signaling pathway, AD,
GIA High and Prostate cancer (Figure 3D).
Log Kp (cm/s) −6.65 cm/s 3.5. Molecular docking
BBB Permeant No The docking analysis performed using CB-Dock2
Abbreviations: OB: Oral availability; BBB: Blood-brain barrier; demonstrated significant interactions between FT and five
DL: Drug-likeness; MW: Molecular weight; Hacc: Number of
H-bond acceptors; Hdon: Number of H-bond donors; Rbon: Number target proteins, underscoring their crucial role in drug-
of rotatable bonds; TPSA: Topological polar surface area; disease interactions for the treatment of MDD. The updated
Log Kp: Logarithm of permeability coefficient; GIA: Gastrointestinal results reveal that FT exhibits high binding affinities with
absorption. the following proteins: GSK3B, with a Vina score of −8.4;
MAOA, with a Vina score of −10.2; ACHE, with a Vina
3.3. PPI of FT score of −9.2; MMP9, with a Vina score of −8.3; and MPO,
Utilizing the STRING database, PPI analysis was carried with a Vina score of −10.2. These findings highlight FT’s
out to identify the FT targets in the context of treating potential as a therapeutic agent in MDD treatment through
MDD, (Figure 2A). A total of 17 target proteins were its interactions with these key targets. In comparison, the
examined, and the resulting data were input into Cytoscape established antidepressant fluoxetine (FLX) shows varying
for topological analysis of the constructed PPI network. To binding affinities across the same targets, with Vina scores
measure the significance of nodes within this network, we of −7.7 for GSK3B, −9.0 for MAOA, −10.0 for ACHE, −8.5
utilized the CytoNCA application to select the top genes for MMP9, and −8.0 for MPO. Notably, FT demonstrates
(Figures 2B and C). Through this comprehensive analysis, superior binding affinities, particularly with MAOA and
we successfully identified 10 critical target proteins as follows: MPO, suggesting that it may offer a competitive advantage
glycogen synthase kinase 3 beta (GSK3B), monoamine in targeting these proteins compared to FLX. This
oxidase A (MAOA), acetylcholinesterase (ACHE), matrix comparative analysis not only emphasizes FT’s therapeutic
metalloproteinase 9 (MMP9), myeloperoxidase (MPO), potential but also provides a clearer evaluation of its
xanthine dehydrogenase (XDH), matrix metalloproteinase efficacy in the context of existing treatments for MDD
2 (MMP2), adenosine triphosphate-binding cassette sub- (Figure 4 and Table A1).
family B member 1 (ABCB1), cyclin-dependent kinase
5 (CDK5), and CDK5 regulatory subunit 1 (CDK5R1) 4. Discussion
(Figure 2C and detailed in Table 2). MDD is a complex condition linked to numerous
physiological disturbances, including heightened
3.4. Molecular mechanisms of FT neuroinflammation. Growing research points to
We performed GO and KEGG analyses to identify the inflammatory pathways, especially the nuclear factor kappa
possible molecular mechanisms underlying FT’s effects B (NF-κB) pathway, as key contributors to the development
in the treatment of MDD. The BP analysis revealed a total of MDD. 15,30 In individuals with MDD, increased levels of
of 1,000 items, highlighting the top five components, proinflammatory cytokines, such as interleukin-1 beta,
namely, response to amyloid-beta, excitatory post-synaptic interleukin-6 (IL-6), and tumor necrosis factor α (TNFα),

Volume 4 Issue 1 (2025) 5 doi: 10.36922/gpd.4846