TY - JOUR
T1 - Modifications on the tetrahydroquinoline scaffold targeting a phenylalanine cluster on GPER as antiproliferative compounds against renal, liver and pancreatic cancer cells
AU - Méndez-Luna, David
AU - Morelos-Garnica, Loreley Araceli
AU - García-Vázquez, Juan Benjamín
AU - Bello, Martiniano
AU - Padilla-Martínez, Itzia Irene
AU - Fragoso-Vázquez, Manuel Jonathan
AU - González, Alfonso Dueñas
AU - De Pedro, Nuria
AU - Gómez-Vidal, José Antonio
AU - Mendoza-Figueroa, Humberto Lubriel
AU - Correa-Basurto, José
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/1
Y1 - 2021/1
N2 - 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 con-centrations. 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.
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 con-centrations. 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.
KW - Antiproliferative
KW - Docking
KW - GPER
KW - Molecular dynamics simulations
KW - Suzuki–Miyaura cross-coupling
KW - Tetrahydroquinoline scaffold
UR - http://www.scopus.com/inward/record.url?scp=85099377851&partnerID=8YFLogxK
U2 - 10.3390/ph14010049
DO - 10.3390/ph14010049
M3 - Artículo
C2 - 33435260
AN - SCOPUS:85099377851
SN - 1424-8247
VL - 14
SP - 1
EP - 19
JO - Pharmaceuticals
JF - Pharmaceuticals
IS - 1
M1 - 49
ER -