Page 158 - EJMO-9-1

Eurasian Journal of Medicine and
Oncology
Potential of flavonoids against glioblastoma

3.3. Molecular docking benzene ring. In contrast, Figure 2C demonstrates that

Molecular docking was conducted in XP mode for both the CCL formed a single hydrogen bond with Tyr272
phytochemicals (Compound 1 and Compound 2) against and cyclohexylamine, indicating greater stability for
10 target proteins, identified by their respective PDB IDs: Compound 2 within the complex with 3O96. In addition,
2FD6, 3ZYA, 4XMB, 5NHJ, 5OQ4, 6NUQ, 6RNU, 4WZV, hydrophobic interactions were observed between
6ZIR, and 3O96. The initial step in the docking process Compound 2 and the CCL; specifically, the residue
involved verifying the docking protocol by calculating the Trp80 formed hydrophobic π-π stacking interactions
all-atom RMSD of the original control ligand (CCL) and with hydroxy-dihydro-pyranone and the aromatic
moiety of the ring. Moreover, hydrophobic π-alkyl
the redocked CCL for all target proteins. The resulting
RMSD values were ≤ 2 Å for all proteins, confirming the interactions were identified with residues Val270 and
validity of the docking protocol. Leu210. The following residues contributed to van der
Waals interactions: Ala212, Leu213, Arg206, Tyr263,
The docking results are presented in Table 3, which His207, Leu264, Lys268, Gln79, Asn54, Val271, Tyr273,
illustrates the docking scores of the bioactive flavonoids and Asp292. These interactions collectively enhance the
(Compounds 1 and 2) in comparison to their control stability of the Compound 2 complex, suggesting that it
ligands (CCLs). Notably, Compound 1 achieved the may serve as a superior inhibitor compared to the CCL
highest docking scores against most of the target proteins. against the AKT1 protein. These findings collectively
Remarkably, Compound 1 exhibited the highest highlighted the potential of Compound 1 and Compound
docking score of −10.391 kcal/mol against mTOR (PDB 2 as promising inhibitors of glioblastoma-related targets,
ID: 5OQ4), while Compound 2 achieved a score of −10.28 specifically mTOR and AKT1, which are critical for
kcal/mol against the same target. Conversely, Compound 2 glioblastoma progression.
emerged as a top scorer against AKT1 (PDB ID: 3O96) with Figure 2B displays the interaction of Compound 1 with
a score of -10.458 kcal/mol. The docking scores suggested mTOR (PDB ID: 5OQ4), showcasing the hydrogen bond
that Compounds 1 and 2 have strong binding interactions formations between residue Glu880 and one of the -OH
against mTOR and AKT1, respectively. groups attached to the catechol, as well as between residue
The strong binding affinities of both compounds were Val882 and both -OH groups of catechol. Furthermore,
further visualized using Discovery Studio, as depicted in residues Asp836 and Lys833 formed hydrogen bonds
Figure 2. with the -OH group of phenol and the oxygen of the
ether attached to the aromatic ring, suggesting enhanced
Figure 2A illustrates the interactions of Compound 2 binding affinity and stability of the complex. Notably,
with AKT1 (PDB ID: 3O96), highlighting the formation Lys833 also participated in the formation of hydrophobic
of two conventional hydrogen bonds between amino acid π-alkyl interactions with other amino acid residues. An
residues Thr211 and Ser205 with the hydroxyl groups electrostatic π-sulfur interaction was identified, formed
(-OH) positioned at the ortho position of the catechol by residue Met953 within the benzoid moiety of the ring,
which plays a critical role in stabilizing the complex.
Table 3. Docking scores of bioactive flavonoids (Compounds In contrast, in the CCL (Figure 2D), only conventional
1 and 2) against 10 putative glioblastoma target proteins, hydrogen bonds and π-alkyl interactions were observed,
compared with their co‑crystal ligands (CCLs) with the van der Waals forces being more prominent in

Target Docking scores (kcal/mol) the Compound 1 complex than in the CCL. These findings
proteins CCL 1 2 indicate that Compound 1 holds promise as a potential
2FD6 −3.914 −3.923 −2.885 inhibitor for the mTOR protein.
3ZYA −12.131 −9.034 −6.914 3.4. Prediction of absorption, distribution,
4WZV −9.253 −9.096 −7.959 metabolism, and excretion properties
4XMB −9.017 −6.894 −6.646 The evaluation of the physicochemical properties of
5NHJ −11.889 −10.185 −8.502 Compounds 1 and 2 (Table 4) indicates compliance with
5OQ4 −8.484 −10.391 −10.28 LRF. Specifically, the molecular weights of both compounds
6NUQ −7.86 −3.911 −4.787 are ≤500 g/mol, the number of hydrogen bond donors is
6RNU −5.404 −6.824 −7.152 ≤5, and the number of hydrogen bond acceptors is ≤10. In
addition, the total polar surface area (TPSA) is ≤140 Ų for
6ZIR −3.028 −2.717 −3.999 both phytochemicals, suggesting their potential as drug-
3O96 −10.086 −10.208 −10.458 like candidates.

Volume 9 Issue 1 (2025) 150 doi: 10.36922/ejmo.5768