Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2020-11-06 , DOI: 10.1016/j.bmcl.2020.127672 Ajay Pal 1 , James F Curtin 2 , Gemma K Kinsella 2
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- 26.69µM). 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.
中文翻译:
电子和体外筛选靶向GPR120的潜在抗癌候选药物
最近,G蛋白偶联受体GPR120被认为是结直肠癌(CRC)和其他癌症治疗的新靶标。在这项研究中,使用基于计算机对接的虚拟筛选(DBVS),结构-活性关系(SAR)和体外结合的方法,生成了GPR120S(短同种型)的同源性模型,以鉴定靶向GPR120受体的潜在抗癌化合物。筛选方法。使用开发的GPR120S模型筛选合成化学物质的SPECS数据库(约350,000个),以识别与正构结合口袋结合的分子,然后进行AutoDock SMINA刚柔对接方案。
然后在体外测试了最佳的13种命中分子,以评估它们对SW480 –表达GPR120的人CRC细胞系的细胞毒活性。测试化合物1( 3-(4-(甲基苯基))-2-([(2-2-氧-2-苯基乙基)硫烷基] -5,6-二氢螺(苯并[h]喹唑啉5,1'-环戊烷) - 4(3H) -酮)显示出对与微摩尔亲和力细胞生长(约90%的抑制作用IC 50)= 23.21-26.69μM。最终,化合物1的SAR分析导致从SPECS数据库中鉴定出活性更高的化合物,在基于细胞的细胞毒性测定中显示出更好的疗效– 5(IC 50 = 5.89-6.715 µM),同时显着降低了化合物1的细胞毒性作用。在GPR120-siRNA预处理的SW480细胞中观察到5。
生成的GPR120S同源性模型和这项工作进行的SAR分析发现了一种潜在的化学支架,二氢螺环(苯并[h]喹唑啉-5,1'-环戊烷)-4(3H)-one,这将有助于未来的抗用于CRC管理的抗癌药物开发。