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Updated: Dec 1, 2025
Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
In silico and in vitro screening for potential anticancer candidates targeting GPR120
Ajay Pal1, James F Curtin2, Gemma K Kinsella2
1School of Food Science and Environmental Health, College of Sciences and Health, Technological University Dublin, Dublin D07 ADY7, Ireland; Environmental Sustainability and Health Institute (ESHI), Grangegorman, Technological University Dublin, Dublin D07 H6K8, Ireland.
Abstract:
The G-protein coupled receptor - GPR120 has recently been implicated as a novel target for colorectal cancer (CRC) and other cancer managements. In this study, a homology model of GPR120S (short isoform) was generated to identify potential anti-cancer compounds targeting the GPR120 receptor using a combined in silico docking-based virtual screening (DBVS), structure-activity relationships (SAR) and in vitro screening approach. SPECS database of synthetic chemical compounds (~350,000) was screened using the developed GPR120S model to identify molecules binding to the orthosteric binding pocket followed by an AutoDock SMINA rigid-flexible docking protocol. The best 13 hit molecules were then tested in vitro to evaluate their cytotoxic activity against SW480 - human CRC cell line expressing GPR120. The test compound 1 (3-(4-methylphenyl)-2-[(2-oxo-2-phenylethyl)sulfanyl]-5,6-dihydrospiro(benzo[h]quinazoline-5,1'-cyclopentane)-4(3H)-one) showed ~ 90% inhibitory effects on cell growth with micromolar affinities (IC50 = 23.21-26.69 µM). Finally, SAR analysis of compound 1 led to the identification of a more active compound from the SPECS database showing better efficacy during cell-based cytotoxicity assay -5 (IC50 = 5.89-6.715 µM), while a significant reduction in cytotoxic effects of 5 was observed in GPR120-siRNA pre-treated SW480 cells. The GPR120S homology model generated, and SAR analysis conducted by this work discovered a potential chemical scaffold, dihydrospiro(benzo[h]quinazoline-5,1'-cyclopentane)-4(3H)-one, which will aid future research on anti-cancer drug development for CRC management.
Insights
Researchers identified a novel G-protein coupled receptor (GPR120) target for colorectal cancer (CRC) drug development. In silico screening and in vitro assays revealed a potent compound with significant CRC cell growth inhibition, validating GPR120 as a therapeutic target.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Oncology
Background:
- G-protein coupled receptor 120 (GPR120) is an emerging target for colorectal cancer (CRC) therapy.
- Developing novel anti-cancer agents requires innovative screening and validation strategies.
Purpose of the Study:
- To generate a homology model of the GPR120 short isoform (GPR120S) for drug discovery.
- To identify and validate potential anti-cancer compounds targeting GPR120 using computational and experimental methods.
Main Methods:
- Homology modeling of GPR120S.
- In silico docking-based virtual screening (DBVS) of the SPECS chemical database (~350,000 compounds).
- In vitro cytotoxicity assays using the SW480 human CRC cell line and GPR120-siRNA.
Main Results:
- A homology model of GPR120S was successfully generated and used for virtual screening.
- Compound 1 exhibited significant cytotoxic effects against SW480 cells (IC50 = 23.21-26.69 µM).
- Structure-activity relationship (SAR) analysis led to a more potent compound (IC50 = 5.89-6.715 µM) with GPR120-dependent activity.
Conclusions:
- The GPR120S homology model and SAR analysis are effective for discovering anti-cancer drug candidates.
- A novel dihydrospiro(benzo[h]quinazoline-5,1'-cyclopentane)-4(3H)-one scaffold shows promise for CRC drug development.
- GPR120 is a validated therapeutic target for colorectal cancer management.
