Mangiferin-Mediated Sirtuin Modulation in Chemotherapy-Induced Cognitive Impairment: Insights from Computational Analysis

Abstract

Context: Chemobrain, known as chemotherapy-induced cognitive impairment (CICI), is among the adverse effects of chemotherapy frequently observed in chronic breast cancer survivors. This condition is primarily attributed to the increased presence of free oxygen radicals and inflammatory cytokines both peripherally and centrally. SIRT1, a highly conserved evolutionary regulator, plays a pivotal role in protecting organisms from oxidative stress. Notably, elevated levels of SIRT1 are expressed in the hippocampal regions of the brain, a critical structure closely associated with learning and memory in the central nervous system. This correlation suggests that SIRT1 is implicated in the regulation of various cognitive disability models. Therefore, modulating SIRT1 activity has the potential to mitigate CICI by reducing oxidative stress markers within the brain. Method: The current study involves molecular docking of Mangiferin and other phytochemicals previously established as activators of human SIRT1 protein. Subsequently, molecular dynamics simulations are conducted using the phytochemical that exhibited the highest docking score compared to others. These investigations encompass several key steps, including protein selection, protein and ligand preparation, receptor grid generation, ligand docking, calculation of binding free energy, and molecular dynamic simulation by using using Maestro version 12.1 using Schrodinger, LLC.