TY  - JOUR
T1  - Computationally Guided Optimization of a Tetrahydroquinoline Scaffold for Targeting GPER in Cancer Cells
A1  - Daniel R. Wilson
A1  - Laura M. Chen
A1  - Thomas K. Nguyen
JF  - Pharmaceutical Sciences and Drug Design
JO  - Pharm Sci Drug Des
SN  - 3062-4428
Y1  - 2025
VL  - 5
IS  - 1
DO  - 10.51847/qlTwWfAme8
SP  - 360
EP  - 376
N2  - Computational and informatics-driven methodologies have become essential components of modern drug discovery, particularly for the development of targeted anticancer agents with improved selectivity and minimized adverse effects. In the present study, three previously unreported compounds were conceived through a structure-based design strategy and subsequently synthesized. In silico screening predicted favorable pharmacokinetic and toxicity-related properties, as well as strong binding affinity toward the G protein-coupled estrogen receptor (GPER). These computational findings were supported by experimental antiproliferative evaluations conducted in multiple cancer cell lines. To elucidate the molecular basis of receptor–ligand recognition, molecular docking was integrated with molecular dynamics simulations and molecular mechanics/generalized Born surface area (MMGBSA) calculations. The resulting models indicated stable ligand accommodation within the GPER binding cavity, mediated by critical interactions with a cluster of aromatic residues comprising F206, F208 and F278, which are known to govern ligand recognition at this receptor. Biological assessment using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay demonstrated that compounds 4, 5 and 7 significantly reduced the viability of MIA Paca-2, RCC4-VA and Hep G2 cancer cells at micromolar concentrations. Collectively, these findings suggest that strategic modification of the GPER pharmacophore can yield novel ligands capable of effectively engaging the receptor and exerting growth-suppressive effects in nontraditional GPER-expressing cancer models.
UR  - https://galaxypub.co/article/computationally-guided-optimization-of-a-tetrahydroquinoline-scaffold-for-targeting-gper-in-cancer-c-oholwmqib8or2ge
ER  -