Pharmacophore-based virtual screening from phytocannabinoids as antagonist r-CB1.

Search for new pharmacological alternatives for obesity is based on the design and development of compounds that can aid in weight loss so that they can be used safely and effectively over a long period while maintaining their function. The endocannabinoid system is related to obesity by increasing orexigenic signals and reducing satiety signals. Cannabis sativa is a medicinal plant of polypharmaceutical potential that has been widely studied for various medicinal purposes. The in silico evaluation of their natural cannabinoids (also called phytocannabinoids) for anti-obesity purpose stems from the existence of synthetic cannabinoid compounds that have already presented this result, but which did not guarantee patient safety. In order to find new molecules from C. sativa phytocannabinoids, with the potential to interact peripherally with the pharmacological target cannabinoid receptor 1, a pharmacophore-based virtual screening was performed, including the evaluation of physicochemical, pharmacokinetic, toxicological predictions and molecular docking. The results obtained from the ZINC12 database pointed to Zinc 69 (ZINC33053402) and Zinc 70 (ZINC19084698) molecules as promising anti-obesity agents. Molecular dynamics (MD) studies disclose that both complexes were stable by analyzing the RMSD (root mean square deviation) values, and the binding free energy values demonstrate that the selected structures can interact and inhibit their catalytic activity.

Potential Implications of Vouacapan Compounds for Insecticidal Activity: An In Silico Study.

BACKGROUND: From the fruits and seeds of the species of Pterodon, it is possible to obtain two main products: essential oil and oleoresin. In oleoresin, numerous vouacapan compounds have been demonstrated to have biological potential, including insecticidal activity. OBJECTIVE: In silico studies were performed to identify potential candidates for natural insecticides among the vouacapans present in the genus Pterodon. MATERIALS AND METHODS: Molecular docking and molecular dynamics studies were performed to analyze the interaction of vouacapan compounds with acetylcholinesterase of Drosophila melanogaster. Pharmacokinetic parameters regarding physicochemical properties, plasma protein binding, and activity in the central nervous system were evaluated. The toxicological properties of the selected molecules were predicted using malathion as the reference compound. RESULTS: 6α,7ß-dimethoxivouacapan-17-ene (15) showed a high number of interactions and scores in molecular docking studies. These results suggested that this compound exhibits an inhibitory activity of the enzyme acetylcholinesterase. This compound showed the best results regarding physicochemical properties, besides presenting low cutaneous permeability values, suggesting null absorption. Molecular dynamics studies demonstrated few conformational changes in the structure of the complex formed by compound 4 and acetylcholinesterase enzyme throughout the simulation time. CONCLUSION: It was determined that compound 4 (vouacapan 6α,7ß,17ß,19-tetraol) could be an excellent candidate for usage as a natural insecticide.

Theoretical Study of Monoamine Oxidase B Inhibitors as Drug Candidates for Treatment of Parkinson's Disease.

BACKGROUND: Drugs used for Parkinson's disease (PD) are mainly responsible for only relieving major symptoms, but may present several side effects that are typical of such pharmacological treatment. METHODS: This study aimed to use in silico methods for drug designing inhibitors of the PD therapeutic target, monoamine oxidase B (MAO-B). Thus, 20 MAO-B inhibitors from the BindingDB database were selected followed by a calculation of their descriptors at DFT B3LYP/6-31G** level of theory. RESULTS: Statistical analysis considering a Pearson correlation matrix led to the selection of electrophilicity index as a descriptor related to the biological activity of inhibitors. Furthermore, based on the prediction of suitable ADME/Tox properties, the molecule CID 54583085 was selected as a template to carry out structural modifications to obtain 3 analogues, whereas molecules B and C showed significant improvement in mutagenicity and carcinogenicity, in relation to the template. CONCLUSION: Thus, it is concluded that the proposed modifications led us to satisfactory results, since there was an improvement in the toxicological properties of molecules, however, further studies must be carried out to evaluate their biological activities as possible MAO-B inhibitors for PD treatment.

Parkinson's Disease: A Review from Pathophysiology to Treatment.

Parkinson's Disease (PD) is the second most common neurodegenerative disease in the elderly population, with a higher prevalence in men, independent of race and social class; it affects approximately 1.5 to 2.0% of the elderly population over 60 years and 4% for those over 80 years of age. PD is caused by the necrosis of dopaminergic neurons in the substantia nigra, which is the brain region responsible for the synthesis of the neurotransmitter dopamine (DA), resulting in its decrease in the synaptic cleft. The monoamine oxidase B (MAO-B) degrades dopamine, promoting the glutamate accumulation and oxidative stress with the release of free radicals, causing excitotoxicity. The PD symptoms are progressive physical limitations such as rigidity, bradykinesia, tremor, postural instability and disability in functional performance. Considering that there are no laboratory tests, biomarkers or imaging studies to confirm the disease, the diagnosis of PD is made by analyzing the motor features. There is no cure for PD, and the pharmacological treatment consists of a dopaminergic supplement with levodopa, COMT inhibitors, anticholinergics agents, dopaminergic agonists, and inhibitors of MAO-B, which basically aims to control the symptoms, enabling better functional mobility and increasing life expectancy of the treated PD patients. Due to the importance and increasing prevalence of PD in the world, this study reviews information on the pathophysiology, symptomatology as well as the most current and relevant treatments of PD patients.

Cannabinoid Type†1 Receptor (CB1) Ligands with Therapeutic Potential for Withdrawal Syndrome in Chemical Dependents of Cannabis sativa.

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.

A QSAR, pharmacokinetic and toxicological study of new artemisinin compounds with anticancer activity.

The Density Functional Theory (DFT) method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with different degrees of cytotoxicity against the human hepatocellular carcinoma HepG2 line. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to select the most important descriptors related to anticancer activity. The significant molecular descriptors related to the compounds with anticancer activity were the ALOGPS_log, Mor29m, IC5 and GAP energy. The Pearson correlation between activity and most important descriptors were used for the regression partial least squares (PLS) and principal component regression (PCR) models built. The regression PLS and PCR were very close, with variation between PLS and PCR of R(2) = ± 0.0106, R(2)(ajust) = ± 0.0125, s = ± 0.0234, F(4,11) = ± 12.7802, Q(2) = ± 0.0088, SEV = ± 0.0132, PRESS = ± 0.4808 and SPRESS = ± 0.0057. These models were used to predict the anticancer activity of eight new artemisinin compounds (test set) with unknown activity, and for these new compounds were predicted pharmacokinetic properties: human intestinal absorption (HIA), cellular permeability (PCaCO2), cell permeability Maden Darby Canine Kidney (PMDCK), skin permeability (P(Skin)), plasma protein binding (PPB) and penetration of the blood-brain barrier (C(Brain/Blood)), and toxicological: mutagenicity and carcinogenicity. The test set showed for two new artemisinin compounds satisfactory results for anticancer activity and pharmacokinetic and toxicological properties. Consequently, further studies need be done to evaluate the different proposals as well as their actions, toxicity, and potential use for treatment of cancers.

Biodiversity as a source of bioactive compounds against snakebites.

Snakebites are a frequently neglected public health issue in tropical and subtropical countries. According to the World Health Organization, 5 million people are bitten annually including up to 2.5 million envenomations. Treatment with antivenom serum remains the only specific therapy for snakebite envenomation. However, it is heterologous and therefore liable to cause adverse reactions, such as early anaphylactic, pyrogenic and delayed reactions. In order to develop alternatives to the current therapy, researchers have been looking for natural products and plant extracts with antimyotoxic, anti-hemorrhagic and anti-inflammatory properties. Especially due to the role the physiopathological processes triggered by snake toxins, play in paralysis, bleeding disorders, kidney failure and tissue damage. Considering the fact that studies involving snake toxins and specific inhibitors, particularly on a molecular level, are the main key to understand neutralization mechanisms and to propose models or prototypes for an alternative therapy, this article presents efforts made by the scientific community in order to produce validated data regarding 87 compounds and plant extracts obtained from 79 species. These plants, which belong to 63 genera and 40 families, have been used by traditional medicine as alternatives or complements to the current serum therapy.

Phospholipase A2 inhibitors isolated from medicinal plants: alternative treatment against snakebites.

Many plants are used in traditional medicine as active agents against various effects of snake bites. Phospholipase A2 enzymes are commonly found in venoms of snakes of the Viperidae and Elaphidae families, which are their main components. This article presents an overview of inhibitors isolated from plants, which show antiophidian properties.

A SAR and QSAR study of new artemisinin compounds with antimalarial activity.

The Hartree-Fock method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with antimalarial activity. Maps of molecular electrostatic potential (MEPs) and molecular docking were used to investigate the interaction between ligands and the receptor (heme). Principal component analysis and hierarchical cluster analysis were employed to select the most important descriptors related to activity. The correlation between biological activity and molecular properties was obtained using the partial least squares and principal component regression methods. The regression PLS and PCR models built in this study were also used to predict the antimalarial activity of 30 new artemisinin compounds with unknown activity. The models obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with antimalarial activity were the hydration energy (HE), the charge on the O11 oxygen atom (QO11), the torsion angle O1-O2-Fe-N2 (D2) and the maximum rate of R/Sanderson Electronegativity (RTe+). These variables led to a physical and structural explanation of the molecular properties that should be selected for when designing new ligands to be used as antimalarial agents.