Swain_2025_J.Chem.Inf.Model__

Alzheimer's disease (AD), often referred to as the "diabetes of the brain", is intricately linked to insulin resistance. Metformin, a first-line antidiabetic drug, has been anticipated as a potential treatment for AD and is currently undergoing phase 3 clinical trials. The potential success of metformin in treating AD could herald a new era in the management of this debilitating disease, providing hope for millions of people affected worldwide. Despite this fact, the precise molecular mechanisms underlying the therapeutic effects of metformin on AD remain poorly understood. To pursue this, in this present work, we implement a comprehensive computational approach combining classical molecular dynamics (MD) simulations and the advanced enhanced sampling technique funnel metadynamics (FM) to explore the dynamics and affinity of metformin and acetylcholinesterase (AChE), a novel target for AD. The MD and FM simulations suggest that metformin induces significant configurational changes within the AChE, resulting in weak and nonspecific binding. Furthermore, the presence of metformin alters the conformational landscape of AChE causing the emergence of metastable states and less rigid binding patterns. The binding energies for the metformin-AChE complex are -4.89 +/- 1.2 kcal/mol and -1.68 +/- 0.2 kcal/mol, as estimated through the molecular mechanics Poisson-Boltzmann surface area (MMPBSA) and FM approaches, respectively. To elucidate the binding energy relevance calculated by MMPBSA and FM approach with experimental inhibitory potency, deltaG(exp) is calculated using IC(50) value reported in prior experimental studies. deltaG(exp) is estimated to be -3.59 kcal/mol. A comparison of these binding energy values with different methods highlights the moderate inhibitory potency of metformin toward AChE. This work provides molecular-level insights emphasizing the dynamic configurational changes induced by metformin within AChE and underscores its translational potential in the repurposing of AD.