Exploring the molecular interactions and binding affinity of resveratrol and calcitriol with RAGE and its intracellular proteins and kinases involved in colorectal cancer

Abstract

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