Department of Pharmacy, Health and Nutritional Sciences (Department of Excellence 2018-2022), University of Calabria, Rende, Italy.
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):377-383. doi: 10.1080/14756366.2020.1864629.
A classical drug repurposing approach was applied to find new putative GPR40 allosteric binders. A two-step computational protocol was set up, based on an initial pharmacophoric-based virtual screening of the DrugBank database of known drugs, followed by docking simulations to confirm the interactions between the prioritised compounds and GPR40. The best-ranked entries showed binding poses comparable to that of TAK-875, a known allosteric agonist of GPR40. Three of them (tazarotenic acid, bezafibrate, and efaproxiral) affect insulin secretion in pancreatic INS-1 832/13 β-cells with EC in the nanomolar concentration (5.73, 14.2, and 13.5 nM, respectively). Given the involvement of GPR40 in type 2 diabetes, the new GPR40 modulators represent a promising tool for therapeutic intervention towards this disease. The ability to affect GPR40 was further assessed in human breast cancer MCF-7 cells in which this receptor positively regulates growth activities (EC values were 5.6, 21, and 14 nM, respectively).
采用经典的药物重定位方法来寻找新的潜在 GPR40 变构结合物。建立了一个两步计算方案，基于已知药物的 DrugBank 数据库的初始基于药效团的虚拟筛选，然后进行对接模拟以确认优先化合物与 GPR40 之间的相互作用。排名最高的化合物显示出与 TAK-875（一种已知的 GPR40 变构激动剂）相当的结合构象。其中三种（他扎罗汀酸、苯扎贝特和 efaproxiral）以纳摩尔浓度（分别为 5.73、14.2 和 13.5 nM）影响胰腺 INS-1 832/13 β细胞中的胰岛素分泌。鉴于 GPR40 参与 2 型糖尿病，新的 GPR40 调节剂代表了针对该疾病的治疗干预的有前途的工具。在人类乳腺癌 MCF-7 细胞中进一步评估了对 GPR40 的作用，其中该受体正向调节生长活性（EC 值分别为 5.6、21 和 14 nM）。
