Journal
PHARMACEUTICALS
Volume 14, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/ph14010049
Keywords
GPER; docking; molecular dynamics simulations; Suzuki– Miyaura cross-coupling; tetrahydroquinoline scaffold; antiproliferative
Categories
Funding
- CONACYT [CB-254600, APN-782]
- CONACYT (SEP-CONACYT-ANUIES-ECOS Francia) [296636]
- Instituto Politecnico Nacional
- COFAA-SIP/IPN
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The study designed and synthesized three new compounds with high affinity for the GPER binding site, which showed growth inhibitory activity in cancer cell lines without side effects. In silico studies revealed the binding modes and energetic features of the compounds on GPER, indicating potential for new compounds with growth inhibitory activities against nonconventional GPER cell models.
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.
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