UNASSIGNED: GIT1/β-Pix inhibitors were identified from ChemBridge by virtual screening. Briefly, the modeling of GIT1 was performed and the establishment of GIT1/β-Pix binding pocket enabled the virtual screening to identify the inhibitor. In addition, direct binding of the candidate molecules to GIT1 was detected by biolayer interferometry (BLI) to discover the hit compound. Furthermore, the inhibitory effect on invasion of stomach and colon cancer cells in vitro was carried out by the transwell assay and detection of epithelial-mesenchymal transition (EMT)-related proteins. Finally, the binding mode of hit compound to GIT1 was estimated by molecular dynamics simulation to analyze the key amino residues to guide further optimization.
UNASSIGNED: We selected the top 50 compounds from the ChemBridge library by virtual screening. Then, by skeleton similarity analysis nine compounds were selected for further study. Furthermore, the direct interaction of nine compounds to GIT1 was detected by BLI to obtain the best affinitive compound. Finally, 17302836 was successfully identified (KD = 84.1±2.0 μM). In vitro tests on 17302836 showed significant anti-invasion effect on gastric cancer and colorectal cancer.
UNASSIGNED: We discovered a new GIT1/β-Pix inhibitor (17302836) against gastrointestinal cancer invasion and metastasis. This study provides a promising candidate for developing new GIT1/β-Pix inhibitors for tumor treatment.
■通过虚拟筛选从ChemBridge中鉴定出GIT1/β-Pix抑制剂。简而言之,我们对GIT1进行了建模,GIT1/β-Pix结合袋的建立使得能够进行虚拟筛选以鉴定抑制剂.此外,通过生物层干涉法(BLI)检测候选分子与GIT1的直接结合,以发现命中化合物。此外,通过transwell实验和上皮-间质转化(EMT)相关蛋白的检测,对体外胃癌和结肠癌细胞的侵袭具有抑制作用。最后,通过分子动力学模拟估计命中化合物与GIT1的结合模式,分析关键氨基残基,指导进一步优化。
■我们通过虚拟筛选从ChemBridge库中选择了前50种化合物。然后,通过骨架相似性分析,选择了9个化合物进行进一步研究。此外,通过BLI检测9个化合物与GIT1的直接相互作用,以获得最佳亲合化合物。最后,成功鉴定出17302836(KD=84.1±2.0μM)。对17302836的体外试验显示对胃癌和结直肠癌有显著的抗侵袭感化。
■我们发现了一种新的GIT1/β-Pix抑制剂(17302836),可对抗胃肠道肿瘤的侵袭和转移。这项研究为开发用于肿瘤治疗的新型GIT1/β-Pix抑制剂提供了有希望的候选者。