Breast cancer is a complex disease comprising multiple deregulated signaling pathways, oxidative stress, metabolic rewiring, and resistance to therapy. The multi-target therapeutic efficacy of β-sitosterol against breast cancer was studied using an integrated approach that combined network pharmacology, molecular docking, molecular dynamics simulations, and ADMET. Out of which 98 common targets were identified between β-sitosterol and breast cancer, wherein PPARG, TNF, ABL kinase, HIF1A, ESR1, PGR, PPARA, MAPK8, AR, and ESR2 are the key hub genes. The enrichment analysis showed that β-Sitosterol had strong binding affinities towards ABL kinase (-9.7 kcal/mol), PPARA (-9.5 kcal/mol), MAPK8 (-8.7 kcal/mol), and PPARG (-8.6 kcal/mol). Indeed, molecular dynamics simulations were performed for 1000 ns at the molecular level, and the progesterone receptor (PGR) proved to be the most dynamically stable target, as the β-sitosterol-PGR complex remained stable throughout the simulation. The predicted ADMET profile was good. The results suggest that β-sitosterol acts on multiple targets in breast cancer and identify PGR, a target not strongly favored by docking alone, as an important therapeutic target revealed through extended molecular dynamics simulation.
Alma Khan, Srinivas Ganjipete, Prabu Kumar Seetharaman et al.· Computational biology and ch...· 0 citations
Reactive oxygen species and endogenous antioxidants are essential for
normal cellular metabolism; however, an imbalance between them causes oxidative stress,
which significantly contributes to the onset and progression of various diseases, including neurodegenerative,
cancer, and cardiovascular disorders. Thus, designing new antioxidant scaffolds
is an important research priority. Among the many heterocycles, 3,4-dihydropyrimidin-2(1H)-
one (DHPM) derivatives are particularly appealing because of their structural diversity and simple
synthesis route through the Biginelli reaction. This study aimed to identify potent antioxidant
DHPM derivatives using a structure-based computational approach.
The target protein (PDB ID: 4IQK) was prepared and optimised for docking studies.
Standard antioxidant drugs were retrieved from the PubChem database. The generated compounds
were subjected to molecular modeling to evaluate their binding affinities with the target
protein. In addition, the pharmacokinetic and ADME/T properties of the compounds were assessed
using pkCSM.
Among the thirty DHPM derivatives evaluated, six derivatives had strong binding affinities,
with values between -7.9 and -8.0 kcal/mol. Compound DHPM 22 was the most powerful
lead among them. It exhibited a better binding affinity of -8.0 kcal/mol because it formed
hydrogen bonds, π-π stacking, and hydrophobic interactions with the protein's active site. Furthermore,
ADME/T analysis confirmed the favorable drug-likeness and pharmacokinetic properties
of the selected compounds.
The docking and ADME/T studies of the 3,4-dihydropyrimidin-2(1H)-one derivatives
showed favorable antioxidant activity against the Keap protein with PDB ID: 4IQK.
Amongst the designed compounds, compound DHPM 22 showed the highest binding affinity (-
8.0 kcal/mol), which was comparable to the standard 4-bromoflavone (-8.5 kcal/mol). This enhanced
binding affinity can be attributed to the formation of conventional hydrogen bonds with
Gly367A, Val465A, and Gly464A, hydrophobic interactions with Val418A, Ile416A, Ala366A,
Leu557A, Leu365A, Val604A, and Val606A, as well as a π-alkyl interaction with Ile559A, collectively
contributing to the stabilization of the ligand within the active site. Compounds DHPM
3 and DHPM 29 also showed favorable binding scores of -7.9 and -7.8 kcal/mol, respectively.
The structure-activity relationship suggests that the electron-withdrawing groups like fluoro and
bromo enhanced binding affinity, whereas bulky polar substituents reduced the antioxidant activity.
Overall, the present study demonstrates that DHPM derivatives, specifically
DHPM 22, may represent a promising lead for the development of new antioxidant derivatives.
Further experimental studies are recommended to confirm their biological activities and therapeutic
potential.
Chanda Ranjan, A. Mahesh, B. C. et al.· Current Computer - Aided Dru...· 0 citations
