Cannabis sativa withdrawal syndrome is characterized mainly by psychological symptoms. By using computational tools, the aim of this study was to propose drug candidates for treating withdrawal syndrome based on the natural ligands of the cannabinoid type 1 receptor (CB1). One compound in particular, 2‐n‐butyl‐5‐n‐pentylbenzene‐1,3‐diol (ZINC1730183, also known as stemphol), showed positive predictions as a human CB1 ligand and for facile synthetic accessibility. Therefore, ZINC1730183 is a favorable candidate scaffold for further research into pharmacotherapeutic alternatives to treat C. sativa withdrawal syndrome.

Background: Alzheimer's disease is a progressive neurodegenerative process of multifactorial characteristics. This disease follows the natural aging process, affecting mainly people over 65 years. Pharmacotherapeutic treatment currently combats symptoms related to cognitive function. Several targets begin to attract the interest of the scientific community to develop new drug candidates, which have better pharmacokinetic and lower toxicity parameters. Objective: The present study aims to design new candidates for acetylcholinesterase/β-secretase (AChE/BACE1) multitarget inhibitor drugs. Method: 17 natural products were selected from the literature with anticholinesterase activity and 1 synthetic molecule with inhibitory activity for BACE1. Subsequently, the molecular docking study was performed, followed by the derivation of the pharmacophoric pattern and prediction of pharmacokinetic and toxicological properties. Finally, the hybrid prototype was designed. Results: All selected molecules showed interactions with their respective target enzymes. Derivation of the pharmacophoric pattern from molecules that interacted with the AChE enzyme resulted in 3 pharmacophoric regions: an aromatic ring, an electron-acceptor region and a hydrophobic region. The molecules showed good pharmacokinetic and toxicological results, showing no warnings of mutagenicity and/or carcinogenicity. After the hybridization process, three hybrid molecules were obtained, which showed inhibitory activity for both targets. Conclusion: It is concluded that research in the field of medicinal chemistry is advancing towards the discovery of new drug candidates that bring a better quality of life to patients with AD.

: The GSK-3β enzyme is related to neuronal cell degeneration presented in Alzheimer’s Disease (AD). The objective of this research was to propose analogues of GSK-3β inhibitors through the search for inhibitors of this enzyme, derivation of the pharmacophore patterns of those inhibitors, molecular docking, ADME/Tox prediction, molecular modifi- cations and prediction of synthetic viability. Six analogues were obtained from the inhibitor CID 57399952, since it presents favorable ADME properties and, as disadvantage, only presents mutagenicity. After modifications, all analogues presented absence of alerts of mutagenic and carcinogenic activity, both for rats and mouse, likewise all presented low risks alerts for inhibition of hERG and medium prediction of synthetic viability. It is concluded that the analogues to GSK-3β inhibitors were optimized in relation to the toxicity of template, being presented as promising drug candidates for Alzheimer’s disease treatment.

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, where the molecular docking and pharmacokinetic and toxicological predictions was 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 lycoramine presented potential for use in the planning and development of new anti-Alzheimer drug candidates.

Alzheimer Farmacoterapia Acetilcolinesterase BACE1 GSK3β. A Doença de Alzheimer (DA) provém de um processo neurodegenerativo progressivo de característica multifatorial que acompanha o processo de envelhecimento natural do ser humano. O tratamento farmacoterapêutico, atualmente empregado, consiste, basicamente, em controlar os sintomas, principalmente os relacionados com a função cognitiva, isto é, memória e aprendizado. Devido a sua característica multifatorial, vários alvos começam a despertar o interesse da comunidade científica, no intuito de desenvolver novos candidatos a fármacos, que apresentem melhores parâmetros farmacocinéticos e menor toxicidade. Este artigo tem como objetivo demonstrar, através de uma revisão bibliográfica, diferentes alvos para o tratamento farmacoterapêutico, tais como: acetilcolinesterase (AChE), beta secretase (BACE1) e a glicogênio sintase quinase 3β; bem como moléculas que já apresentam comprovada capacidade de interação e inibição com estes alvos, inclusive, as que já estão em fases de testes clínicos. Conclui-se que as pesquisas estão avançando, cada vez mais, em direção ao descobrimento de novos candidatos a fármacos com maior seletividade e que possam trazer uma melhor qualidade de vida aos pacientes portadores de DA.