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

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

Volume: 18 Issue: 11

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 and José Correa-Basurto*

Affiliation:

• Departamento de Quimica Organica, Escuela Nacional de Ciencias, Biologicas, Instituto Politecnico Nacional, Prolongacion de Carpio y Plan de Ayala, 11340, Ciudad de Mexico,Mexico

• Laboratorio de Diseno y Desarrollo de Nuevos Farmacos e Innovación Biotecnologica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politecnico Nacional, Plan de San Luis y Díaz Miron, 11340 Ciudad de Mexico,Mexico

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

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.

Cite this article as:

Martínez-Muñoz Alberto , Prestegui-Martel Berenice , Méndez-Luna David, Fragoso-Vázquez J. Manuel *, García-Sánchez Rubén José, Bello Martiniano , Martínez-Archundia Marlet , Chávez-Blanco Alma , Dueñas-González Alfonso , Mendoza-Lujambio Irene, Trujillo-Ferrara José and Correa-Basurto José*, Selection of a GPER1 Ligand via Ligand-based Virtual Screening Coupled to Molecular Dynamics Simulations and Its Anti-proliferative Effects on Breast Cancer Cells, Anti-Cancer Agents in Medicinal Chemistry 2018; 18 (11) . https://dx.doi.org/10.2174/1871520618666180510121431