@misc{10481/66576,
year = {2021},
url = {http://hdl.handle.net/10481/66576},
abstract = {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.},
organization = {CONACYT (Grants: CB-254600, APN-782 and
SEP-CONACYT-ANUIES-ECOS Francia: 296636)},
organization = {Instituto Politécnico Nacional (Grant: Proyectos
Insignia IPN-2015)},
organization = {COFAA-SIP/IPN},
publisher = {MDPI},
keywords = {GPER},
keywords = {Docking},
keywords = {Molecular dynamics simulations},
keywords = {Suzuki–Miyaura cross-coupling},
keywords = {Tetrahydroquinoline scaffold},
keywords = {Antiproliferative},
title = {Modifications on the Tetrahydroquinoline Scaffold Targeting a Phenylalanine Cluster on GPER as Antiproliferative Compounds against Renal, Liver and Pancreatic Cancer Cells},
doi = {10.3390/ph14010049},
author = {Méndez Luna, David and Gómez Vidal, José Antonio},
}