Computational insights in repurposing a 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 (AD) 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 drugs to combat this degenerative condition. Histone deacetylase 2 (HDAC2) represents a promising epigenetic target for neurodegenerative diseases. So, for this study, we chose HDAC2 as the targeted protein. 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 approved food and drug administration (FDA) drugs utilized in clinical trials for AD. Molecular docking was carried out for the 58 compounds. The 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. However, its exact significance in treating or preventing AD is still being studied. Molecular dynamics (MD) and molecular mechanics with generalized born and surface area solvation (MM-GBSA)/interaction entropy (IE) calculations were carried out to study the structural stability of the complexes. Umbrella sampling (US) techniques are a cutting-edge drug development method to understand more about the interactions between protein and ligand. π–π stacking interactions play a major role in helping the ligand to bind in the zinc bounding domain of the protein. From these analyses, 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.