Research Article: Chemical profile of Lippia thymoides, evaluation of the acetylcholinesterase inhibitory activity of its essential oil, and molecular docking and molecular dynamics simulations

Date Published: March 8, 2019

Publisher: Public Library of Science

Author(s): Sebastião Gomes Silva, Renato Araújo da Costa, Mozaniel Santana de Oliveira, Jorddy Neves da Cruz, Pablo Luis B. Figueiredo, Davi do Socorro Barros Brasil, Lidiane Diniz Nascimento, Antônio Maia de Jesus Chaves Neto, Raul Nunes de Carvalho Junior, Eloisa Helena de Aguiar Andrade, Marco Bonizzoni.


The essential oils of the fresh and dry flowers, leaves, branches, and roots of Lippia thymoides were obtained by hydrodistillation and analyzed using gas chromatography (GC) and GC–mass spectrometry (MS). The acetylcholinesterase inhibitory activity of the essential oil of fresh leaves was investigated on silica gel plates. The interactions of the key compounds with acetylcholinesterase were simulated by molecular docking and molecular dynamics studies. In total, 75 compounds were identified, and oxygenated monoterpenes were the dominant components of all the plant parts, ranging from 19.48% to 84.99%. In the roots, the main compounds were saturated and unsaturated fatty acids, having contents varying from 39.5% to 32.17%, respectively. In the evaluation of the anticholinesterase activity, the essential oils (detection limit (DL) = 0.1 ng/spot) were found to be about ten times less active than that of physostigmine (DL = 0.01ng/spot), whereas thymol and thymol acetate presented DL values each of 0.01 ng/spot, equivalent to that of the positive control. Based on the docking and molecular dynamics studies, thymol and thymol acetate interact with the catalytic residues Ser203 and His447 of the active site of acetylcholinesterase. The binding free energies (ΔGbind) for these ligands were -18.49 and -26.88 kcal/mol, demonstrating that the ligands are able to interact with the protein and inhibit their catalytic activity.

Partial Text

Alzheimer’s disease is considered one of the major public health problems worldwide and one of the main complications of this pathology is the activity deficit of cholinergic neurons. This fact can be reversed and/or attenuated by elevating the levels of the neurotransmitter acetylcholine in the neuronal synaptic area. The use of cholinesterase inhibitors is an effective therapeutic approach [1]. The inhibitors increase the availability of neurotransmitters by inhibiting their main catalytic enzymes, acetyl- and butyrylcholinesterase, thus diminishing the cholinergic deficit and relieving the symptoms of Alzheimer’s patients [2]. The oldest inhibitor of these enzymes is physostigmine, an alkaloid of the shrub Physostigma venenosum Balf [3]. Synthetic and semisynthetic inhibitors, such as galantamine, donepezil, tacrine, and rivastigmine, can also be used, but these drugs have disadvantages such as short half-lives and adverse side effects including hepatotoxicity and gastrointestinal irritation [1,4,5]. This has encouraged a search for new inhibitors from natural sources, and some examples are the secondary metabolites present in essential oils [1,4,6–8].

Thymol is the main constituent in the essential oil from the flowers (37.86% DFL; 48.04% FFL), leaves (58.9% DLE; 66.33% FLE), and branches (63.59% FB; 66.2% DB) of L. thymoides, and the essential oil of the fresh leaves had the highest content of this oxygenated monoterpene. In the roots, hexadecanoic acid (palmitic acid) was the main constituent (38.02% DR; 40.92% DF) of the oil. The essential oil of the fresh leaves (DL = 0.1 ng/spot) and two of its mains components, thymol (DL = 0.01 ng/spot) and thymol acetate (DL = 0.01 ng/spot), showed inhibitory activity against acetylcholinesterase on TLC layers.




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