Selection of a GPER1 Ligand via Ligand-based Virtual Screening Coupled to Molecular Dynamics Simulations and Its Anti-proliferative Effects on Breast Cancer Cells

Author(s): Alberto Martínez-Muñoz , Berenice Prestegui-Martel , David Méndez-Luna , Manuel J. Fragoso-Vázquez* , José Rubén García-Sánchez , Martiniano Bello , Marlet Martínez-Archundia , Alma Chávez-Blanco , Alfonso Dueñas-González , Irene Mendoza-Lujambio , José Trujillo-Ferrara , José Correa-Basurto* .

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 18 , Issue 11 , 2018

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Abstract:

Background: Recent reports have demonstrated the role of the G Protein-Coupled Estrogen Receptor 1 (GPER1) on the proliferation of breast cancer. The coupling of GPER1 to estrogen triggers cellular signaling pathways related to cell proliferation.

Objective: Develop new therapeutic strategies against breast cancer.

Method: We performed in silico studies to explore the binding mechanism of a set of G15 /G1 analogue compounds. We included a carboxyl group instead of the acetyl group from G1 to form amides with several moieties to increase affinity on GPER1. The designed ligands were submitted to ligand-based and structure-based virtual screening to get insights into the binding mechanism of the best designed compound and phenol red on GPER1.

Results: According to the in silico studies, the best molecule was named G1-PABA ((3aS,4R,9bR)-4-(6- bromobenzo[d][1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-carboxylic acid). It was synthesized and assayed in vitro in breast cancer (MCF-7 and MDA-MB-231) and normal (MCF-10A) cell lines. Experimental studies showed that the target compound was able to decrease cell proliferation, IC50 values of 15.93 µM, 52.92 µM and 32.45 µM in the MCF-7, MDA-MB-231 and MCF-10A cell lines, respectively, after 72 h of treatment. The compound showed better IC50 values without phenol red, suggesting that phenol red interfere with the G1-PABA action at GPER1, as observed through in silico studies, which is present in MCF-7 cells according to PCR studies and explains the cell proliferation effects.

Conclusion: Concentration-dependent inhibition of cell proliferation occurred with G1-PABA in the assayed cell lines and could be due to its action on GPER1.

Keywords: GPER1, breast cancer, virtual screening, molecular docking, cell growth inhibitor, anti-proliferation, MCF-7, MDA-MB-231.

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Article Details

VOLUME: 18
ISSUE: 11
Year: 2018
Page: [1629 - 1638]
Pages: 10
DOI: 10.2174/1871520618666180510121431
Price: $58

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