Abstract
Acetylcholinesterase (AChE) inhibition is a key element in enhancing cholinergic transmission and subsequently relieving major symptoms of several neurological and neuromuscular disorders. Here, the inhibitory potential of geraniol and its mechanism of inhibition against AChE were elucidated in vitro and validated via an in silico study. Our in vitro enzyme inhibition kinetics results show that at increasing concentrations of geraniol and substrate, Vmax did not change significantly, but Km increased, which indicates that geraniol is a competitive inhibitor against AChE with an IC50 value 98.06 ± 3.92 µM. All the parameters of the ADME study revealed that geraniol is an acceptable drug candidate. A docking study showed that the binding energy of geraniol (−5.6 kcal mol−1) was lower than that of acetylcholine (−4.1 kcal mol−1) with AChE, which exhibited around a 12.58-fold higher binding affinity of geraniol. Furthermore, molecular dynamics simulation revealed that the RMSD of AChE alone or in complex with geraniol fluctuated within acceptable limits throughout the simulation. The mean RMSF value of the complex ensures that the overall conformation of the protein remains conserved. The average values of Rg, MolSA, SASA, and PSA of the complex were 3.16 Å, 204.78, 9.13, and 51.58 Å2, respectively. We found that the total SSE of AChE in the complex was 38.84% (α-helix: 26.57% and β-sheets: 12.27%) and remained consistent throughout the simulation. These findings suggest that geraniol remained inside the binding cavity of AChE in a stable conformation. Further in vivo investigation is required to fully characterize the pharmacokinetic properties, optimization of dose administration, and efficacy of this plant-based natural compound.
Highlights
IntroductionA significant deficit in cholinergic transmission may result in various illnesses such as cognitive decline through deterioration of cholinergic neuron-rich regions and decrease in the ACh level, which is believed to be associated with memory loss, agitation, and apathy in Alzheimer disease (AD) [2]; gait dysfunction, mainly because of an imbalance between striatal ACh and dopamine as in Parkinson disease (PD) [3]; and fatigable muscle weakness due to antibody-mediated blockade of acetylcholine receptors (AChR) at the neuromuscular junction, which abolishes the naturally occurring ‘safety factor’ of synaptic transmission during myasthenia gravis (MG) [4]
Our results show the inhibitory potential of tacrine and geraniol in terms of IC50 value results show the inhibitory potential tacrine and geraniol in terms of IC
The results show that geraniol has an acceptable range of physicochemical properties, drug-likeness, and pharmacokinetics (Table 1), which confirmed its suitability as a drug candidate, and it was selected for molecular docking and molecular dynamics simulation analysis
Summary
A significant deficit in cholinergic transmission may result in various illnesses such as cognitive decline through deterioration of cholinergic neuron-rich regions and decrease in the ACh level, which is believed to be associated with memory loss, agitation, and apathy in Alzheimer disease (AD) [2]; gait dysfunction, mainly because of an imbalance between striatal ACh and dopamine as in Parkinson disease (PD) [3]; and fatigable muscle weakness due to antibody-mediated blockade of AChR at the neuromuscular junction, which abolishes the naturally occurring ‘safety factor’ of synaptic transmission during myasthenia gravis (MG) [4] Cholinesterase enzymes such as AChE further decreased the concentration of ACh by hydrolyzing it [1]. There is significant interest in the improvement of effective treatment to reduce the symptoms of disease and stop the degeneration of neurons that cause the disease
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