Chromatographic profile, in silico and in vivo study of the pharmacokinetic and toxicological properties of major constituent present in kefir, the kefiran.

Kefiran is a polysaccharide present in kefir grains that have been widely explored due to its potential health benefits. The objective of this work was to characterize and quantify the components present in the ethanolic extract of milk kefir grains; to study its pharmacokinetic and toxicological properties in silico and evaluate the acute toxicity of the kefiran in zebrafish. The prediction of pharmacokinetic properties was performed by QikProp software. In silico toxicity assessment was performed using the DEREK (deductive estimate of risk from existing knowledge) software. In the chromatographic, kefiran was identified as the major component. Results showed that the kefiran had low human oral absorption and intestinal absorption its due poor solubility profile; low logP value, indicating its lipophilicity and the low MDCK and Caco-2 cells permability, and unable to cross the blood-brain barrier. Kefiran did not present any structural warning for in silico toxicity. In zebrafish, the dose of 2,000 mg/kg of kefiran produced nonsignificant alterations in the analyzed organs. It can be said then that kefiran has an acceptable degree of safety for use in the development of drugs or functional foods. Further research such as in vivo testing to confirm its pharmacological potential is currently underway.

Design of Multitarget Natural Products Analogs with Potential Anti-Alzheimer's Activity.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition and the most common type of dementia among the elderly. The enzymes acetylcholinesterase (AChE) and nitric oxide synthase (NOS) have a pivotal role in the pathophysiology of this disease. OBJECTIVE: This study aimed to select medicinal plant-derived molecules with reported inhibition of AChE and design optimized molecules that could inhibit not only AChE, but also NOS, potentially increasing its efficacy against AD. METHODS: 24 compounds were selected from the literature based on their known AChE inhibitory activity. Then, we performed molecular orbital calculations, maps of electrostatic potential, molecular docking study, identification of the pharmacophoric pattern, evaluation of pharmacokinetic and toxicological properties of these molecules. Next, ten analogs were generated for each molecule to optimize their effect where the best molecules of natural products had failed. RESULTS: The most relevant correlation was between HOMO and GAP in the correlation matrix of the molecules' descriptors. The pharmacophoric group's derivation found the following pharmacophoric features: two hydrogen bond acceptors and one aromatic ring. The studied molecules interacted with the active site of AChE through hydrophobic and hydrogen bonds and with NOS through hydrogen interactions only but in a meaningful manner. In the pharmacokinetic and toxicological prediction, the compounds showed satisfactory results. CONCLUSION: The design of natural products analogs demonstrated good affinities with the pharmacological targets AChE and NOS, with satisfactory pharmacokinetics and toxicology profiles. Thus, the results could identify promising molecules for treating Alzheimer's disease.

Hypoglycemic Activity of Aqueous Extract of Latex from Hancornia speciosa Gomes: A Study in Zebrafish and In Silico.

Hancornia speciosa Gomes is a tree native to Brazil and has therapeutic potential for several diseases. Ethnopharmacological surveys have reported that the plant is used as a hypoglycemic agent and to lose weight. This study aimed to evaluate the effects of the aqueous extract from H. speciosa latex (LxHs) in a zebrafish model of diabetes. The extract was evaluated through high-performance thin-layer chromatography (HTPLC), nuclear magnetic resonance (NMR), and Fourier-transform infrared spectroscopy (FT-IR). We then tested treatments with LxHs (500, 1000, and 1500 mg/kg) by assessing blood glucose levels in alloxan-induced diabetic animals, and metformin was used as a control. The toxicity was evaluated through histopathology of the pancreas and biochemical assessment of serum levels of AST, ALT, creatinine, and urea. The extract was also assessed for acute toxicity through several parameters in embryos and adult animals. Finally, we performed in silico analysis through the SEA server and docking using the software GOLD. The phytochemical study showed the compounds cornoside, dihydrocornoide, and 1-O-methyl-myoinositol (bornesitol). The treatment with all doses of LxHs significantly decreased alloxan-induced hyperglycemia without any significant histological or biochemical abnormalities. No significant frequency of teratogenesis was observed in the embryos exposed to the extract, and no significant behavioral changes or deaths were observed in adult animals. In silico, the results showed a potential interaction between inositol and enzymes involved in carbohydrates' metabolism. Overall, the results show a hypoglycemic activity of the extract in vivo, with no apparent toxicity. The computational studies suggest this could be at least partially due to the presence of bornesitol, since inositols can interact with carbohydrates' enzymes.

Virtual screening, ADME/Tox predictions and the drug repurposing concept for future use of old drugs against the COVID-19.

The new Coronavirus (SARS-CoV-2) is the cause of a serious infection in the respiratory tract called COVID-19. Structures of the main protease of SARS-CoV-2 (Mpro), responsible for the replication of the virus, have been solved and quickly made available, thus allowing the design of compounds that could interact with this protease and thus to prevent the progression of the disease by avoiding the viral peptide to be cleaved, so that smaller viral proteins can be released into the host's plasma. These structural data are extremely important for in silico design and development of compounds as well, being possible to quick and effectively identify potential inhibitors addressed to such enzyme's structure. Therefore, in order to identify potential inhibitors for Mpro, we used virtual screening approaches based with the structure of the enzyme and two compounds libraries, targeted to SARS-CoV-2, containing compounds with predicted activity against Mpro. In this way, we selected, through docking studies, the 100 top-ranked compounds, which followed to subsequent studies of pharmacokinetic and toxicity predictions. After all the simulations and predictions here performed, we obtained 10 top-ranked compounds that were again in silico analyzed inside the Mpro catalytic site, together some drugs that are being currently investigated for treatment of COVID-19. After proposing and analyzing the interaction modes of these compounds, we submitted one molecule then selected as template to a 2D similarity study in a database containing drugs approved by FDA and we have found and indicated Apixaban as a potential drug for future treatment of COVID-19.