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Molecular docking and pharmacokinetic and toxicological predictions of natural compounds with anticholinestearase activity
Published: 14 November 2018 by MDPI in 4th International Electronic Conference on Medicinal Chemistry session ECMC-4

Alzheimer's disease (AD) is considered the leading and most common age-related dementia, accounting for 50-60% of cases. The most commonly used pharmacotherapeutic approach for the symptomatic control of AD is anticholinesterase drugs, that is, they have an inhibitory activity on the enzyme acetylcholinesterase (AChE), thus increasing the cerebral levels of the neurotransmitter acetylcholine (Ach). For many years, Traditional Chinese Medicine has been cataloging numerous medicinal plants, which present various pharmacological activities, such as anti-Alzheimer's activity. This variety of plants present compounds that interact with multiple proteins that are involved in several pathways associated with AD. The main objective of this study is an in silico study of 14 natural compounds, for which molecular docking and pharmacokinetic and toxicological predictions were carried out. As a first step the following molecules were selected in the literature: 1,8-cineole, bornil acetate, α-pinene, β-pinene, camphor, cariophilene epoxide, physostigmine, galantamine, γ-terpinene, honokiol, huperzine A, licoramine , magnolol and resveratrol, and later designed with the Chemsketch program and the chemical structures optimized with the Hartree-Fock method and the base function 6-31G ** previously validated in the Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem) and implemented in the Gaussian program 03. The second step was the molecular docking study carried out with the software GOLD 4.1 where it was possible to study the intermolecular interactions among the selected natural products with the amino acids present in the active site of the AChEenzyme, the connections were largely hydrophobic interactions and hydrogen bonds and all 14 molecules showed interactions with the amino acid residues TRP286, PHE295, TYR341, TYR72 present in the catalytic site of the target enzyme, but only 13 presented three or more interactions, predominantly. In order to predict the pharmacokinetic properties of the selected molecules, the QikProp module of the Schrödinger software was used, which computed some important properties such as: molecular weight, polar surface area (PSA), logP, logBB, percentage of human oral absorption, activity predicted in the central nervous system, apparent permeability in cells and MDCK. As a result, all 14 molecules were found to have satisfactory PSA, LogBB, permeability to Caco-2 and MDCK cells, but only 7 molecules were able to cross the blood-brain barrier. The toxicity profile of the 14 molecules selected was performed by the DEREK program, where a total of 19 structural alerts were verified. The molecules that presented these alerts were: camphor, caryophyllene epoxide, physostigmine, honokiol, magnolol and resveratrol. Based on the results presented by the study, the following compounds were found: α-pinene, β-pinene, galantamine, γ-terpinene and licoramine presented potential for use in the planning and development of new anti-Alzheimer drug candidates.

Keywords: Alzheimer's disease; molecular docking; natural compounds; pharmacokinetic predictions; toxicological predictions.