In silico and in vitro screening for potential anticancer candidates targeting GPR120

[Display omitted] •GPR120 (short isoform) homology model used for docking-based virtual screening (DBVS) of ligand database.•Combination approach of in silico and in vitro screening to discover potential anti-cancer compounds targeting GPR120.•Identification of a dihydrospiro(benzo[h]quinazoline-5,1′-cyclopentane)-4(3H)-one scaffold for anti-cancer activity. 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.