结肠直肠癌（CRC）负担在年轻人群中逐渐增加，原因是饮食和生活方式模式的改变。糖基化终末产物（AGEs）是膳食化合物之一，它与蛋白质、脂质和核酸形成复杂的聚集体，扭曲它们的结构和功能。AGE通过AGE受体（RAGE）介导的信号通路触发促肿瘤作用。本研究旨在通过分子对接（MD）、分子动力学模拟（MDS）、MM-PBSA分析和体外研究，从多个水平上针对AGE-RAGE轴信号蛋白和激酶进行CAL和转-resveratrol（RES）的靶向筛选。CAL和RES的分子对接分析显示其与RAGE及其信号蛋白（如NF-kB、PI3K/AKT、ERK1/2和PKC）相比参考抑制剂具有更好的氢键、疏水性和pi-pi堆积作用。MD和MDS研究显示蛋白质-配体复合物稳定且紧凑。利用MM/PBSA分析估计蛋白质-配体复合物的结合自由能，从而评估复合物的整体相互作用自由能，并揭示活性位点内的低结合能。此外，在体外研究中，AGE前体甲基甘氧（MG）对HCT116细胞具有增殖效应，然而，CAL和RES对MG诱导的效应具有抑制作用，其IC50分别为51 nM和110 µM。因此，研究表明CAL和RES可能是AGE-RAGE信号蛋白和激酶的潜在靶点结合位点，可以与化疗药物一起开发CAL与RES作为CRC辅助治疗。由Ramaswamy H. Sarma传达。

Colorectal cancer (CRC) burden is progressively increasing in young population due to dietary and lifestyle pattern. Advanced glycation end products (AGEs), one of the dietary compounds, form complex aggregates with proteins, lipids, and nucleic acids distorting their structure and function. AGE's pro-tumorigenic role is mediated through the receptor for AGEs (RAGE) triggering an array of signaling pathways. The current study aimed to target AGE-RAGE axis signaling proteins and kinases at multiple levels with calcitriol (CAL) and trans-resveratrol (RES) through in silico analysis using molecular docking (MD), molecular dynamic simulation(MDS), MM-PBSA analysis, and in vitro study. In silico analysis of CAL and RES showed significant binding affinity toward RAGE and its signaling proteins such as NF-kB, PI3K/AKT, ERK1/2, and PKC compared to its reference inhibitors through better hydrogen, hydrophobic, pi-pi stacking interactions. MD and MDS studies have revealed stable and compact protein-ligand complexes. Binding free energies of protein-ligand complex were estimated using MM/PBSA analysis thatprovided an assessment of overall interacting free energies of complexes and revealed the presence of low binding energy within the active site. Furthermore, in the in vitro study, methylglyoxal (MG), an AGE-precursor showed a proliferative effect on HCT116, however, CAL and RES showed an inhibitory effect against MG induced effect with an IC50 value of 51 nM and 110 µM respectively. Thus, the study suggests the possible target binding sites of AGE-RAGE signaling proteins and kinases with CAL and RES, thereby exploiting it for developing CAL with RES as adjuvant therapy along with chemo drug for CRC.Communicated by Ramaswamy H. Sarma.