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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:31

Article

Pal, Ajay^1,2  Curtin, James F.¹  Kinsella, Gemma K.¹ 

[1] Technol Univ Dublin, Coll Sci & Hlth, Sch Food Sci & Environm Hlth, Dublin D07 ADY7, Ireland

[2] Technol Univ Dublin, Grangegorman, Environm Sustainabil & Hlth Inst ESHI, Dublin D07 H6K8, Ireland

关键词: Molecular docking;    Virtual screening;    GPCR GPR120;    FFA4 receptor;    Colorectal cancer;   

DOI  :  10.1016/j.bmcl.2020.127672

来源: Elsevier

【 摘 要 】

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 mu M). 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 mu M), 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.

【 授权许可】

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