Modifications on the Tetrahydroquinoline Scaffold Targeting a Phenylalanine Cluster on GPER as Antiproliferative Compounds against Renal, Liver and Pancreatic Cancer Cells

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.

In silico design and cell-based evaluation of two dual anti breast cancer compounds targeting Bcl-2 and GPER

“…Interestingly, both ligands largely share the same binding mode on GPER binding site (Fig. 2 A), reaching entirely the phenylalanine cluster formed by Phe206, Phe208, Phe223, and Phe278, described as key orchestrator of the GPER activity 28 . Additionally, the subtle differences among both binding modes lie in the presence of Gln215 establishing a h-bond with one of the oxygen atoms from the sulfonamide moiety of 6 at a close contact of 3.11 Å (Fig.…”

“…On the chemical basis of a GPER pharmacophore composed of a tetrahydroquinoline scaffold, we previously developed a GPER ligand named G1-PABA 26 – 28 which contains in its structure a carboxylic acid group capable of being modified by an amide bond formation. Taking advantage of that, we proposed functionalizing it by forming an amide bond with nucleophilic amines, which contain chemical moieties in its structure, capable of reaching the Bcl-2 binding site 29 , 30 and, consequently, blocks both GPER and Bcl-2 aberrant activity.…”

“…Synthesis of the GPER pharmacophore (tetrahydroquinoline scaffold), named as G1-PABA, was conducted according to the method described by Dennis M.K. et al 50 , with simple chemical modifications standardized in our work group and described elsewhere 26 – 28 .…”

Comparative G-Protein-Coupled Estrogen Receptor (GPER) Systems in Diabetic and Cancer Conditions: A Review

“…Moreover, emerging in silico data are beginning to uncover the molecular mechanism of GPER-ligand interactions. A phenylalanine cluster at the GPER active site is essential for GPER recognition by its agonists and antagonists and this molecular scaffold is proposed to be the binding site of some synthetic tetrahydroquinoline derivatives that inhibit the proliferation of human renal, liver, and pancreatic cancer cell lines in vitro [150]. The finding thus provides insight into the potential role of GPER in the pharmacological treatment of these cancers.…”

Special Issue “GPCRs: Ligands and beyond 2022”

“…With this study, the authors introduce a novel system which can also be used as a future tool in sense-checking newly resolved structures and planning experimental design. The work by Mendez-Luna and coworkers [3] is a joint investigation combining computational tools and experimental assays in order to design potential drug candidates inhibiting the G protein-coupled estrogen receptor (GPER). Under this context, the authors design three compounds that showed notable inhibitory activity against GPER when tested in nonconventional cell models.…”