RT Journal Article
T1 Modifications on the Tetrahydroquinoline Scaffold Targeting a Phenylalanine Cluster on GPER as Antiproliferative Compounds against Renal, Liver and Pancreatic Cancer Cells.
A1 Méndez-Luna, David
A1 Morelos-Garnica, Loreley Araceli
A1 García-Vázquez, Juan Benjamín
A1 Bello, Martiniano
A1 Padilla-Martínez, Itzia Irene
A1 Fragoso-Vázquez, Manuel Jonathan
A1 Dueñas González, Alfonso
A1 De Pedro, Nuria
A1 Gómez-Vidal, José Antonio
A1 Mendoza-Figueroa, Humberto Lubriel
A1 Correa-Basurto, José
K1 GPER
K1 Suzuki–Miyaura cross-coupling
K1 antiproliferative
K1 docking
K1 molecular dynamics simulations
K1 tetrahydroquinoline scaffold
AB The implementation of chemo- and bioinformatics tools is a crucial step in the design of structure-based drugs, enabling the identification of more specific and effective molecules against cancer without side effects. In this study, three new compounds were designed and synthesized with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-tox) properties and high affinity for the G protein-coupled estrogen receptor (GPER) binding site by in silico methods, which correlated with the growth inhibitory activity tested in a cluster of cancer cell lines. Docking and molecular dynamics (MD) simulations accompanied by a molecular mechanics/generalized Born surface area (MMGBSA) approach yielded the binding modes and energetic features of the proposed compounds on GPER. These in silico studies showed that the compounds reached the GPER binding site, establishing interactions with a phenylalanine cluster (F206, F208 and F278) required for GPER molecular recognition of its agonist and antagonist ligands. Finally, a 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay showed growth inhibitory activity of compounds 4, 5 and 7 in three different cancer cell lines-MIA Paca-2, RCC4-VA and Hep G2-at micromolar concentrations. These new molecules with specific chemical modifications of the GPER pharmacophore open up the possibility of generating new compounds capable of reaching the GPER binding site with potential growth inhibitory activities against nonconventional GPER cell models.
SN 1424-8247
YR 2021
FD 2021-01-10
LK http://hdl.handle.net/10668/16962
UL http://hdl.handle.net/10668/16962
LA en
DS RISalud
RD Apr 19, 2025