Repositioning of Angiotensin II Receptor Blockers for Alzheimer’s Disease: An In-Silico Study

The brain renin-angiotensin-aldosterone system (RAAS), through angiotensin II and its AT1 and AT2 receptors, plays a pivotal role in blood pressure regulation and has been implicated in neurodegenerative processes such as Alzheimer's disease (AD). Angiotensin II receptor blockers (ARBs) inhibit the activation of AT1 receptors, thereby favoring an alternative RAAS pathway mediated by angiotensin IV (Ang-IV) and the AT4 receptor, providing protective effects for the nervous system. In this study, an In-silico evaluation of eight ARBs was performed by molecular docking (AutoDock Vina) and molecular dynamics simulations (AMBER20), assessing their binding affinity and conformational behavior with AT1 and AT2 receptors. Telmisartan and candesartan exhibited the highest affinity for AT1, with binding energies of −10.57 ± 0.12 and −9.83 ± 0.06 kcal/mol, respectively. For AT2, telmisartan showed a binding affinity of −10.60 ± 0.00 kcal/mol, although lower than the control ligand (−13.50 kcal/mol). Molecular dynamics simulations revealed that the AT1-telmisartan and AT1–candesartan complexes maintained structural stability with RMSD values remaining below 2.5 Å. The AT1–telmisartan complex exhibited the smallest radius of gyration (< 20 Å) and a reduced solvent accessible surface area (SASA), suggesting a compact and stable conformation. In contrast, the AT2–telmisartan complex demonstrated increased structural fluctuations (RMSF) within amino acid regions 60 - 75, 105 - 120 and 230 - 245, although overall stability was preserved throughout the 100 ns of simulation. These findings suggest that telmisartan and candesartan are promising candidates for modulating brain RAAS and could be considered as potential agents in Alzheimer's disease. Further in vivo validation is warranted to confirm their neuroprotective effect. HIGHLIGHTS Brain’s renin-angiotensin-aldosterone system through the AT1 and AT2 receptors. Angiotensin II Receptor Blockers associated with Alzheimer’s Disease. Telmisartan and Candesartan showed considerable affinity for AT1 and AT2 receptors. ARBs with AT1 and AT2 receptors presented considerable stability through molecular dynamics.