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.
Anti-Cancer Agents in Medicinal Chemistry
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.
Export Options
About this article
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
DOI https://dx.doi.org/10.2174/1871520618666180510121431 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Pharmacological and Cellular Significance of Triazole-Surrogated Compounds
Current Organic Chemistry Disruption of Circadian Rhythms and Sleep in Critical Illness: Potential Implications for Angiogenesis After Myocardial Infarction. A Review
Current Pharmaceutical Design Tissue Distribution and Systemic Toxicity Evaluation of Raloxifene Targeted Polymeric Micelles of Poly (Styrene-Maleic Acid)-Poly (Amide- Ether-Ester-Imide)-Poly (Ethylene Glycol) Loaded With Docetaxel in Breast Cancer Bearing Mice
Recent Patents on Anti-Cancer Drug Discovery Potential Usage of ING Family Members in Cancer Diagnostics and Molecular Therapy
Current Drug Targets Fibroblast Growth Factors/Fibroblast Growth Factor Receptors as Targets for the Development of Anti-Angiogenesis Strategies
Current Pharmaceutical Design Design, Synthesis, Anti-Proliferative, Anti-microbial, Anti-Angiogenic Activity and In Silico Analysis of Novel Hydrazone Derivatives
Anti-Cancer Agents in Medicinal Chemistry Antisense Oligonucleotides as an Innovative Therapeutic Strategy in the Treatment of High-Grade Gliomas
Recent Patents on CNS Drug Discovery (Discontinued) Sphere Formation Assay is not an Effective Method for Cancer Stem Cell Derivation and Characterization from the Caco-2 Colorectal Cell Line
Current Stem Cell Research & Therapy Bile Acids as Novel Pharmacological Agents: The Interplay Between Gene Polymorphisms, Epigenetic Factors and Drug Response
Current Pharmaceutical Design High-Content Screening and Mechanism-Based Evaluation of Estrogenic Botanical Extracts
Combinatorial Chemistry & High Throughput Screening Double-Edged Sword of Novel Anti-Cancer Treatment: Proteasome Inhibition in the Growth Plate Causes Impairment of Longitudinal Bone Growth
Current Pediatric Reviews Overview of microRNA Target Analysis Tools
Current Bioinformatics Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Induced Dyspepsia
Current Pharmaceutical Design The Role of Proteomics in Osteoarthritis Pathogenesis Research
Current Drug Targets Poly(ADP-Ribosylation): Beneficial Effects of Its Inhibition
Current Enzyme Inhibition Titanium Tetrachloride-mediated Synthesis of Diarylmethanes through the Reaction of Benzyl Alcohol Derivatives with Aromatic Substrates
Current Organic Chemistry Serum Cytokine Profile in Alzheimer's Disease Patients After Ingestion of an Antioxidant Beverage
CNS & Neurological Disorders - Drug Targets Natural Product Inhibitors of Hsp90: Potential Leads for Drug Discovery
Mini-Reviews in Medicinal Chemistry Imaging Primary Brain Tumors by Single-Photon Emission Computerized Tomography (SPECT) with Technetium-99m Sestamibi (MIBI) and Tetrofosmin
Current Medical Imaging Impact of Computational Structure-Based Predictive Toxicology in Drug Discovery
Combinatorial Chemistry & High Throughput Screening