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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.
Pal, A., Curtin, J. & Kinsella, G. (2021) In silico and in vitro screening for potential anticancer candidates targeting GPR120, Bioorg Med Chem Lett, 2021 Jan 1;31:127672. doi: 10.1016/j.bmcl.2020.127672