Computational Insights in Repurposing Cardiovascular Drug for Alzheimer's Disease: The Role of Aromatic Amino Acids in Stabilizing the Drug through π-π Stacking Interaction

Abstract

Alzheimer's disease is a neurological condition that worsens over time and causes linguistic difficulties, cognitive decline, and memory loss. Since AD is a complicated, multifaceted illness, it is critical to identify multi-target medications to combat this degenerative condition. HDAC2 represents a promising and visually striking epigenetic target to address neurodegenerative diseases. So, we chose HDAC2 as the targeted protein for this study. Repurposing drugs has many advantages, including reduced costs and high profits. There is a lower probability of malfunction because the unique drug candidate has previously completed numerous investigations. In this study, we have taken 58 clinically FDA-approved drugs which are utilized in the clinical trials for AD. Molecular docking was carried out for the 58 compounds. Telmisartan drug has the highest binding score of -9.4 kcal mol-1. The angiotensin II receptor blocker (ARB) Telmisartan has demonstrated some promise in AD research as of the last update in January 2022, but its exact significance in treating or preventing AD is still being studied. MD and MM-GBSA/IE calculations were carried out to study the structural stability of the complexes. Umbrella sampling techniques are known as a cutting-edge method in drug development to understand more about the interactions between ligands and their target proteins. The π−π stacking interactions play a major role in helping the ligand to bind in the zinc bounding domain of the protein. From this study, we conclude that telmisartan which is a cardiovascular drug is more potent than the other drugs to treat AD. The anti-inflammatory, neuroprotective, and blood-brain barrier-crossing qualities of telmisartan make it a promising therapeutic agent for AD; however, more research, including larger clinical trials, is needed to determine the drug's precise role in treating AD.