Exploring Metformin’s Therapeutic Potential for Alzheimer’s Disease: An In-Silico Perspective Using Well-Tempered Funnel Metadynamics

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, ΔGexp is calculated using
IC50 value reported in prior experimental studies. ΔGexp 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.