从硅到台式:cosmosiin作为PD-1/PDL-1免疫检查点抑制剂,通过DFT、网络药理学分析和分子对接综合实验验证

IF 4.6 3区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY
RSC Advances Pub Date : 2025-07-02 DOI:10.1039/D5RA03831F
Reem I. Alsantali, Abdulaziz M. Almohyawi, Manzoor A. Rather, Jan M. Mir, N. A. Dangroo, Faisal A. Almalki, Taibi Ben Hadda, Rabab S. Jassas, Sultan I. Alkubaysi and Saleh A. Ahmed
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引用次数: 0

摘要

本研究利用计算化学、网络药理学、生物信息学等方法研究了黄酮类化合物宇宙素对乳腺癌(BC)的抗pd -1/PD-L1抑制潜力,并进行了实验验证。密度泛函理论(DFT)的计算是用高斯09和6-311G/B3LYP的形式来评估宇宙素的物理化学性质。cosmsiin的潜在靶点是通过SuperPred、Stitch和SwissTargetPrediction数据库确定的,而bc相关靶点是通过访问GeneCards获得的。使用Venny 2.0进行重叠分析,发现宇宙素的38个靶点和乳腺癌的1314个靶点之间有25个共同靶点。CytoHubba分析突出了10个枢纽基因,其中PTGS2、NFKB1和CDK5最为显著。分子动力学模拟证实,宇宙素与CDK5(−8.5 kcal mol−1)、NFKB1(−7.6 kcal mol−1)和PTGS2(−9.6 kcal mol−1)稳定结合。GEPIA分析将这些基因的表达与乳腺癌的生存结果和疾病分期联系起来。实验中,宇宙素对MCF-7(乳腺癌)和MCF-10(非致瘤性)细胞进行了检测。使用MTT试验评估细胞毒性,显示MCF-7细胞活力降低的剂量依赖性,对MCF-10细胞的影响最小,因此表现出选择性细胞毒性。相衬显微镜显示处理过的MCF-7细胞形态学改变。膜联蛋白V/PI流式细胞术证实早期和晚期凋亡增加,而EdU掺入实验显示DNA合成减少,增殖减少。Transwell实验表明,在较高浓度下,细胞迁移的抑制率高达81%。Western blotting验证了CDK5、NFKB1和PTGS2的下调,与计算预测一致。这些发现强调了宇宙素的选择性,多靶向抗癌活性,特别是通过PTGS2, NFKB1和CDK5,支持其对乳腺癌的治疗作用,对细胞凋亡,增殖和细胞迁移具有有利作用,同时与存活和免疫浸润结果相关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

From silico to benchtop: cosmosiin as a PD-1/PDL-1 immune checkpoint inhibitor revealed through DFT, network pharmacology analysis, and molecular docking integrated experimental verification

From silico to benchtop: cosmosiin as a PD-1/PDL-1 immune checkpoint inhibitor revealed through DFT, network pharmacology analysis, and molecular docking integrated experimental verification

This study investigated the anti-PD-1/PD-L1 inhibition potential of the flavonoid cosmosiin against breast cancer (BC) using computational chemistry, network pharmacology, bioinformatics, and validated by experimental assays. Execution of Density Functional Theory (DFT) calculations was achieved by GAUSSIAN 09 with the 6-311G/B3LYP formalism to assess cosmosiin's physicochemical properties. Potential targets of cosmosiin were identified through SuperPred, Stitch, and SwissTargetPrediction databases, while BC-allied targets were sourced by accessing GeneCards. Overlapping analysis using Venny 2.0 identified 25 common targets between 38 targets of cosmosiin and 1314 targets of breast cancer. CytoHubba analysis highlighted 10 hub genes, with PTGS2, NFKB1, and CDK5 being the most significant. Molecular docking revealed stable binding of cosmosiin to CDK5 (−8.5 kcal mol−1), NFKB1 (−7.6 kcal mol−1), and PTGS2 (−9.6 kcal mol−1), confirmed by molecular dynamics simulations. GEPIA analysis linked the expression of these genes to survival outcomes and disease stage in breast cancer. Experimentally, cosmosiin was tested on MCF-7 (breast cancer) and MCF-10 (non-tumorigenic) cells. Cytotoxicity was evaluated using the MTT assay, showing dose-dependent viability reduction in MCF-7 cells with minimal impact on MCF-10 cells, thus exhibiting selective cytotoxicity. Phase-contrast microscopy revealed altered morphology in treated MCF-7 cells. Annexin V/PI flow cytometry confirmed increased early and late apoptosis, while EdU incorporation assays indicated decreased DNA synthesis and reduced proliferation. Transwell assays demonstrated up to 81% inhibition of cell migration at higher concentrations. Western blotting validated downregulation of CDK5, NFKB1, and PTGS2, aligning with computational predictions. These findings highlight selective, multi-targeted anticancer activity of cosmosiin, particularly through PTGS2, NFKB1, and CDK5, supporting its therapeutic potency for breast cancer with favorable effects on apoptosis, proliferation, and cell migration, while correlating with survival and immune infiltration outcomes.

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来源期刊
RSC Advances
RSC Advances chemical sciences-
CiteScore
7.50
自引率
2.60%
发文量
3116
审稿时长
1.6 months
期刊介绍: An international, peer-reviewed journal covering all of the chemical sciences, including multidisciplinary and emerging areas. RSC Advances is a gold open access journal allowing researchers free access to research articles, and offering an affordable open access publishing option for authors around the world.
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