Pharmacoinformatic screening of phytoconstituent and evaluation of its anti-PDAC effect using <i>in vitro</i> studies

With no prominent treatment for pancreatic ductal adenocarcinoma (PDAC) in conventional chemotherapy, recent studies have focused on uniting conventional and traditional medicines including plant phytoconstituents. Herein, we used pharmacoinformatic studies to identify potent phytoconstituent as ligand having inhibition activities against canonical anticancer targets, and evaluated its effect on PDAC cell lines. SwissTargetPrediction and SuperPred tools were utilized to segregate protein targets of ligand in humans, following which FunRich was applied to garner its targets in PDAC. STRING analysis predicted protein–protein interactions and dynamic simulation studies confirmed stability of ligand–protein complex. For <i>in vitro</i> cytotoxic potential, ligand treatment at different concentrations was given to PDAC cell lines both alone and combined with gemcitabine, followed by evaluation of effects on migration. Differential gene expression was checked using PCR for evaluating mechanism of cytotoxicity. Results showed pentagalloylglucose (PGG) with highest docking and MMGBSA scores for Cyclooxygenase 2 (Cox2) inhibition site. SwissTargetPrediction and SuperPred analysis detected 40 targets of PGG in PDAC. Simulation data showed stability of protein–ligand complex. In i<i>n vitro</i> experiments Mia-PaCa-2 was more sensitive to PGG than Panc-1. PGG successfully inhibited migration both alone and in combination with gemcitabine. Additionally, PGG treatment induced apoptosis in both the cell lines; but showed antagonism when combined with gemcitabine. In conclusion, our report demonstrates PGG has good binding with Cox2 and showed anti-PDAC activity by inhibiting migration and inducing apoptosis, thus it can be used as a therapy option. But further studies are required to confirm its behaviour as a combination therapy drug. Communicated by Ramaswamy H. Sarma鉴于传统化疗对胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）尚无特效治疗方案，近期研究逐渐聚焦于将常规抗癌疗法与包括植物源药效成分在内的传统药物相结合。本研究通过药理信息学分析，筛选出可靶向经典抗癌靶点的强效植物源药效成分作为配体，并评估其对胰腺导管腺癌细胞系的作用效果。研究借助SwissTargetPrediction与SuperPred工具，筛选该配体在人类中的蛋白靶点；随后通过FunRich工具获取其在胰腺导管腺癌中的相关靶点。STRING蛋白互作分析预测了靶点间的蛋白-蛋白相互作用，分子动力学模拟实验证实了配体-蛋白复合物的结构稳定性。为评估该配体的体外（in vitro）细胞毒活性，本研究以不同浓度的配体单独或联合吉西他滨处理胰腺导管腺癌细胞系，随后检测其对细胞迁移的影响；通过聚合酶链式反应（PCR）检测差异基因表达情况，以解析其细胞毒活性的作用机制。实验结果显示，五没食子酰葡萄糖（pentagalloylglucose, PGG）在环氧合酶2（Cyclooxygenase 2, Cox2）抑制位点的分子对接与MMGBSA结合能评分均为最高。SwissTargetPrediction与SuperPred分析共筛选得到PGG在胰腺导管腺癌中的40个靶点，分子动力学模拟数据证实了PGG与靶点蛋白形成的复合物具有良好结构稳定性。体外实验结果显示，Mia-PaCa-2细胞系对PGG的敏感性高于Panc-1细胞系；PGG可单独或联合吉西他滨有效抑制胰腺导管腺癌细胞的迁移能力。此外，PGG单独处理可诱导两种细胞系发生细胞凋亡，但与吉西他滨联合使用时则表现出拮抗作用。综上，本研究表明PGG可与Cox2形成稳定结合，并通过抑制细胞迁移与诱导凋亡发挥抗胰腺导管腺癌活性，有望成为潜在的治疗选择。但仍需开展进一步研究以验证其作为联合治疗药物的临床应用潜力。本文由Ramaswamy H. Sarma转交

搜集汇总

背景与挑战

背景概述

该数据集通过药物信息学方法筛选植物成分pentagalloylglucose（PGG），并评估其抗胰腺导管腺癌（PDAC）的体外效果。研究发现PGG与Cyclooxygenase 2（Cox2）有高结合亲和力，在体外实验中能抑制PDAC细胞迁移并诱导凋亡，但作为联合疗法药物需进一步验证。数据集包括相关实验数据和图表，支持药物开发研究。