Exploring the Binding Pattern of Geraniol with Acetylcholinesterase through In Silico Docking, Molecular Dynamics Simulation, and In Vitro Enzyme Inhibition Kinetics Studies

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.

Secondary Metabolite Profiling, Antioxidant, Antidiabetic and Neuroprotective Activity of Cestrum nocturnum (Night Scented-Jasmine): Use of In Vitro and In Silico Approach in Determining the Potential Bioactive Compound

“…The MeOH extract was found to be a noncompetitive inhibitor of α-amylase and a competitive inhibitor of AChE ( Figure 4 ). On the contrary, the standard drugs, acarbose and tacrine, showed competitive and noncompetitive inhibition of α-amylase and AChE, respectively, which is in agreement with previous reports [ 32 , 39 ]. It is evident that plant extracts exhibit competitive and noncompetitive inhibition due to the presence of a variety of bioactive compounds [ 59 ].…”

“…Antioxidants from natural sources, such as plants, and their secondary metabolites are efficient quenchers of free radicals and interrupt their production. Their consumption helps in the management of oxidative stress and in preventing the onset of several diseases such as DM and AD [ 2 , 36 , 37 , 38 , 39 ]. Numerous in vitro and in vivo studies have shown that C. nocturnum leaf extracts have antifungal, antibacterial, antidiabetic, and wound healing properties [ 22 , 24 , 27 , 28 , 40 ].…”

“…The absorbance was taken at 1 min intervals. The mode of inhibition was determined according to the Michaelis–Menten kinetics [ 39 ].…”

Homology Modelling, Molecular Docking and Molecular Dynamics Simulation Studies of CALMH1 against Secondary Metabolites of Bauhinia variegata to Treat Alzheimer’s Disease

“…Energy minimisation was achieved using the steepest approach of 8 ps. The machine was balanced at 40 ps when the temperature was raised to 300 K. The simulations at 10 ns were performed at 1 bar and at the temperature of 300 K. Finally, an all-bond restriction was employed to keep the ligand from migrating during molecular dynamics [ 25 ].…”

Soyasapogenol-B as a Potential Multitarget Therapeutic Agent for Neurodegenerative Disorders: Molecular Docking and Dynamics Study

“…As brain-derived neurotrophic factor (BDNF) or abrineurin has a critical role in remodeling the cognitive functions and remodeling of synapses, restoring the BDNF expression could be a therapeutic pathway [10]. Meanwhile, a variety of phytochemicals and natural products, like compounds, have been reported as potent antidiabetic, antimicrobial, antioxidant, gastro-protection, geno-protective, hypolipidemic and neuroprotective agents [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. Studies have also shown good improvements in neurodegenerative diseases through the use of phytochemicals [27], and indicating that phytochemicals, which are chemical compounds extracted from plants, exhibit possible health promotion properties.…”