Modifications on the tetrahydroquinoline scaffold targeting a phenylalanine cluster on GPER as antiproliferative compounds against renal, liver and pancreatic cancer cells

David Méndez-Luna, Loreley Araceli Morelos-Garnica, Juan Benjamín García-Vázquez, Martiniano Bello, Itzia Irene Padilla-Martínez, Manuel Jonathan Fragoso-Vázquez, Alfonso Dueñas González, Nuria De Pedro, José Antonio Gómez-Vidal, Humberto Lubriel Mendoza-Figueroa, José Correa-Basurto

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 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.

Original languageEnglish
Article number49
Pages (from-to)1-19
Number of pages19
JournalPharmaceuticals
Volume14
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • Antiproliferative
  • Docking
  • GPER
  • Molecular dynamics simulations
  • Suzuki–Miyaura cross-coupling
  • Tetrahydroquinoline scaffold

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