Anxiolytic and Anticonvulsant Effects of Fisetin Isolated from Bauhinia pentandra on Adult Zebrafish (Danio rerio).

Anxiety and epilepsy are common worldwide and represent a primary global health concern. Fisetin, a flavonoid isolated from Bauhinia pentandra, has a wide range of biological activities may be a promising alternative to combat diseases related to the central nervous system (CNS). The present study aimed to investigate the anxiolytic and anticonvulsant effects of fisetin on adult zebrafish. Furthermore, molecular docking simulations were performed to improve the results. Fisetin did not present toxicity and caused anxiolytic behavior and delayed seizures in animals. This effect may occur through serotonin neurotransmission at 5-HT3A and/or 5-HT3B receptors. Molecular docking simulations showed that fisetin interacts with the orthosteric site of the 5-HT3A receptor with strong H-bond interactions with the Trp156 residue, with a strong contribution from the catechol ring, a behavior similar to that of the antagonist co-crystallized inhibitor granisetron (CWB). Fisetin may be a promising alternative to combat diseases related to the central nervous system. Keywords anxiety • Bauhinia pentandra • Danio rerio • epilepsy • fisetin.

Withanicandrin Isolated from Datura Ferox Promotes Antinociception by Modulating the Asics and TRPS Channels and Anti-Inflammation in Adult Zebrafish.

This is the first study to analyze the anti-inflammatory and antinociceptive effect of withanicandrin, isolated from Datura Ferox leaves, and the possible mechanism of action involved in adult zebrafish (ZFa). To this end, the animals were treated intraperitoneally (i. p.) with withanicandrin (4; 20 and 40 mg/kg; 20 µL) and subjected to locomotor activity and acute toxicity. Nociception tests were also carried out with chemical agents, in addition to tests to evaluate inflammatory processes induced by κ-Carrageenan 1.5 % and a Molecular Docking study. As a result, withanicandrin reduced nociceptive behavior by capsaicin at a dose of 40 mg/kg and by acid saline at doses of 4 and 40 mg/kg, through neuromodulation of TRPV1 channels and ASICs, identified through blocking the antinociceptive effect of withanicandrin by the antagonists capsazepine and naloxone. Furthermore, withanicandrin caused an anti-inflammatory effect through the reduction of abdominal edema, absence of leukocyte infiltrate in the liver tissue and reduction of ROS in thel liver tissue and presented better affinity energy compared to control morphine (TRPV1) and ibuprofen (COX-1 and COX-2).

Structure-based virtual screening of mangiferin derivatives with antidiabetic action: a molecular docking and dynamics study and MPO-based drug-likeness approach.

Extracts from Mangifera indica leaves and its main component, mangiferin, have proven antidiabetic activity. In this study, mangiferin and its natural derivatives Homomangiferin (HMF), Isomangiferin (IMF), Neomangiferin (NMF), Glucomangiferin (GMF), Mangiferin 6'-gallate (MFG), and Norathyriol (NRT) were compared regarding their action on Diabetes mellitus (DM), employing docking and molecular dynamics (MD) simulations to analyze interactions with the aldose reductase enzyme, the precursor to the conversion of glucose into sorbitol. Notably, HMF showed significant affinity to residues in the active site of the enzyme, including Trp 79, His 110, Trp 111, Phe 122, and Phe 300, with an energy of - 7.2 kcal/mol, observed in the molecular docking simulations. MD reinforced the formation of stable complexes for HMF and MFG with the aldose reductase, with interaction potential energies (IPE) in the order of - 300.812 ± 52 kJ/mol and - 304.812 ± 52 kJ/mol, respectively. The drug-likeness assessment, by multiparameter optimization (MPO), highlighted that HMF and IMF have similarities with polyphenols and glycosidic flavonoids recently patented as antidiabetics, revealing that high polarity (TPSA > 180 Å2) is a favorable property for subcutaneous administration, especially because of the gradual passive cell permeability values in biological tissues, with Papp values estimated at < 10 × 10-6 cm/s. These compounds are metabolically stable against metabolic enzymes, resulting in a low toxic incidence by metabolic activation, corroborating with a lethal dose (LD50) greater than 2000 mg/kg. In this way, HMF showed a systematic alignment between predicted pharmacokinetics and pharmacodynamics, characterizing it as the most favorable substance for inhibiting aldose reductase. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03978-9.

Structure and Ligand Based Virtual Screening and MPO Topological Analysis of Triazolo Thiadiazepine-fused Coumarin Derivatives as Anti-Parkinson Drug Candidates.

Parkinson's disease (PD) is a debilitating condition that can cause locomotor problems in affected patients, such as tremors and body rigidity. PD therapy often includes the use of monoamine oxidase B (MAOB) inhibitors, particularly phenylhalogen compounds and coumarin-based semi-synthetic compounds. The objective of this study was to analyze the structural, pharmacokinetic, and pharmacodynamic profile of a series of Triazolo Thiadiazepine-fused Coumarin Derivatives (TDCDs) against MAOB, in comparison with the inhibitor safinamide. To achieve this goal, we utilized structure-based virtual screening techniques, including target prediction and absorption, distribution, metabolism, and excretion (ADME) prediction based on multi-parameter optimization (MPO) topological analysis, as well as ligand-based virtual screening techniques, such as docking and molecular dynamics. The findings indicate that the TDCDs exhibit structural similarity to other bioactive compounds containing coumarin and MAOB-binding azoles, which are present in the ChEMBL database. The topological analyses suggest that TDCD3 has the best ADME profile, particularly due to the alignment between low lipophilicity and high polarity. The coumarin and triazole portions make a strong contribution to this profile, resulting in a permeability with Papp estimated at 2.15 × 10-5 cm/s, indicating high cell viability. The substance is predicted to be metabolically stable. It is important to note that this is an objective evaluation based on the available data. Molecular docking simulations showed that the ligand has an affinity energy of - 8.075 kcal/mol with MAOB and interacts with biological substrate residues such as Pro102 and Phe103. The results suggest that the compound has a safe profile in relation to the MAOB model, making it a promising active ingredient for the treatment of PD.

Insights of potential trypanocidal effect of the synthetic derivative (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one: in vitro assay, MEV analysis, quantum study, molecular docking, molecular dynamics, MPO analysis, and predictive ADMET.

This study aims to evaluate the antitrypanosomiasis activity of a synthetic dichloro-substituted aminochalcone via in vitro assays against infected cell cultures, as well as a theoretical characterization of pharmacokinetics and pharmacodynamics against the protein targets of the evolutionary cycle of T. cruzi. The in vitro evaluation of parasite proliferation inhibition was performed via cytotoxicity analysis on mammalian host cells, effect on epimastigote and trypomastigote forms, and cell death analysis, while computer simulations characterized the electronic structure of (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one (DCl), the mechanism of action against the proteins of the evolutionary cycle of T. cruzi: Cruzain, Trypanothione reductase, TcGAPDH, and CYP51 by molecular docking and dynamics and predictive pharmacokinetics by MPO-based ADMET. The in vitro tests showed that the DCl LC50 in order of 178.9 ± 23.9 was similar to the BZN, evidencing the effectiveness of chalcone against Trypomastigotes. Molecular docking and dynamics simulations suggest that DCl acts on the active site of the CYP51 receptor, with hydrogen interactions that showed a high degree of occupation, establishing a stable complex with the target. MPO analysis and ADMET prediction tests suggest that the compound presents an alignment between permeability and hepatic clearance, although it presents low metabolic stability. Chalcone showed stable pharmacodynamics against the CYP51 target, but can form reactive metabolites from N-conjugation and C = C epoxidation, as an indication of controlled oral dose, although the estimated LD50 rate > 500 mg/kg is a indicative of low incidence of lethality by ingestion, constituting a promising therapeutic strategy.

Hellebrigenin triggers death of promyelocytic leukemia cells by non-genotoxic ways.

Bufadienolides are digitalis-like aglycones mainly found in skin secretions of toads. Among their biological properties, the mechanisms of antiproliferative action on tumor cells remain unclear for many compounds, including against leukemia cells. Herein, it was evaluated the mechanisms involved in the antiproliferative and genotoxic actions of hellebrigenin on tumor cell lines and in silico capacity to inhibit the human topoisomerase IIa enzyme. Firstly, its cytotoxic action was investigated by colorimetric assays in human tumor and peripheral blood mononuclear cells (PBMC). Next, biochemical and morphological studies were detailed by light microscopy (trypan blue dye exclusion), immunocytochemistry (BrdU uptake), flow cytometry and DNA/chromosomal damages (Cometa and aberrations). Finally, computational modelling was used to search for topoisomerase inhibition. Hellebrigenin reduced proliferation, BrdU incorporation, viability, and membrane integrity of HL-60 leukemia cells. Additionally, it increased G2/M arrest, internucleosomal DNA fragmentation, mitochondrial depolarization, and phosphatidylserine externalization in a concentration-dependent manner. In contrast to doxorubicin, hellebrigenin did not cause DNA strand breaks in HL-60 cell line and lymphocytes, and it interacts with ATPase domain residues of human topoisomerase IIa, generating a complex of hydrophobic and van der Waals interactions and hydrogen bonds. So, hellebrigenin presented potent anti-leukemic activity at concentrations as low as 0.06 µM, a value comparable to the clinical anticancer agent doxorubicin, and caused biochemical changes suggestive of apoptosis without genotoxic/clastogenic-related action, but it probably triggers catalytic inhibition of topoisomerase II. These findings also emphasize toad steroid toxins as promising lead antineoplasic compounds with relatively low cytotoxic action on human normal cells.

Antimicrobial activity of hydralazine against methicillin-resistant and methicillin-susceptible Staphylococcus aureus.

Background: Staphylococcus aureus is a human pathogen responsible for high mortality rates. The development of new antimicrobials is urgent. Materials & methods: The authors evaluated the activity of hydralazine along with its synergism with other drugs and action on biofilms. With regard to action mechanisms, the authors evaluated cell viability, DNA damage and molecular docking. Results: MIC and minimum bactericidal concentration values ranged from 128 to 2048 µg/ml. There was synergism with oxacillin (50%) and vancomycin (25%). Hydralazine reduced the viability of biofilms by 50%. After exposure to hydralazine 2× MIC, 58.78% of the cells were unviable, 62.07% were TUNEL positive and 27.03% presented damage in the comet assay (p < 0.05). Hydralazine showed affinity for DNA gyrase and TyrRS. Conclusion: Hydralazine is a potential antibacterial.

Staphylococcus aureus is a bacterium that can cause infection. Infections of S. aureus are becoming difficult to treat, but developing new drugs is a challenge. Repurposing them may be easier. This study looks at the possibility of using hydralazine, a type of medicine used to treat high blood pressure, against S. aureus. The authors found that hydralazine can kill S. aureus and can be used with other antibiotics, including oxacillin and vancomycin. Hydralazine interferes with important processes for the multiplication and survival of this bacterium. These results are preliminary but encouraging. Further studies are needed to confirm the use of hydralazine as a new treatment for S. aureus infections.

Bixinoids Derived from Bixa orellana as a Potential Zika Virus Inhibitor Using Molecular Simulations. Antiviral Effect on the Zika Virus of Bixinoids

Abstract Zika fever is a viral infection of great relevance in public health, especially in tropic regions, in which there is a predominance of mosquitoes of the genus Aedes, vectors of the disease. Microcephaly in neonatal children and Guillain-Barré syndrome in adults can be caused by the action of the Zika virus (ZIKV). Non-structural proteins, such as NS2B, NS3 and NS5, are important pharmacological targets, due to their action in the life cycle. The absence of anti-Zika drugs raises new research, including prospecting for natural products. This work investigated the in silico antiviral activity of bixin and six other derived molecules against the Zika viral proteins NS2B-NS3 and NS5. The optimized structure was subjected to molecular docking to characterize the interaction between bixinoids and ZIKV non-structural proteins, where significant interactions were observed with amino acid residues in the catalytic site in each enzyme. These results suggest that bixin and ethyl bixin has the potential to interfere with the enzymatic activity of NS2B, NS3 and NS5, thus being an indication of being a promising anti-Zika agent.

Evaluation of interactions of silibinin with the proteins ALS3 and SAP5 against Candida albicans / Avaliação das interações da silibinina com as proteínas ALS3 e SAP5 contra Candida albicans

Objective: to evaluate the molecular interaction of silibinin with the targets ALS3 and SAP5. Methodology: Molecular docking protocols were conducted to analyze the binding interaction of silibinin with ALS3 and SAP5. Results: Eleven interactions of ALS3 with silibinin and four with fluconazole were found, while six interactions were observed of SAP5 with silibinin and four with fluconazole. Conclusion: Molecular docking between silibinin and ALS3 identified important interactions, but no significant interactions were observed with SAP5, even though silibinin can exhibit affinity and interactions with other SAP5 sites.

Objetivo: Avaliar a interação molecular da silibinina com os alvos ALS3 e SAP5. Metodologia: Protocolos de docking molecular foram conduzidos para analisar a interação de ligação da silibinina com ALS3 e SAP5. Resultados: Foram encontradas onze interações de ALS3 com silibinina e quatro com fluconazol, enquanto seis interações foram observadas de SAP5 com silibinina e quatro com fluconazol. Conclusão: Docking molecular entre silibinina e ALS3 identificou interações importantes, mas não foram observadas interações significativas com SAP5, embora a silibinina possa apresentar afinidade e interações com outros sítios SAP5.

Study of the interactions of di- and tri-terpenes from Stillingia loranthacea with the enzyme NSP16-NSP10 of SARS-CoV-2 / Estudo das interações de di- e tri-terpenos de Stillingia loranthacea com a enzima NSP16-NSP10 de SARS-CoV-2

Objective: This study aimed to evaluate the interactions of di- and tri-terpenes from Stillingia loranthacea with the enzyme NSP16-NSP10 of SARS-CoV-2, important for viral replication. Methods: The molecular docking technique was used to evaluate this interaction. Results: The analysis showed that the evaluated compounds obtained RMSD values of 0.888 to 1.944 Å and free energy of -6.1 to -9.4 kcal/mol, with the observation of hydrogen bonds, salt bridges, and pi-sulfur, pi-alkyl, and hydrophobic interactions. Conclusion: Thus, the results obtained show the potential of the compounds analyzed against the selected target. Since computer simulations are only an initial step in projects for the development of antiviral drugs, this study provides important data for future research.

Objetivo: avaliar as interações de di- e tri-terpenos de Stillingia loranthacea com a enzima NSP16-NSP10 de SARS-CoV-2, importante para a replicação viral. Métodos: A técnica de docking molecular foi utilizada para avaliar essa interação. Resultados: A análise mostrou que os compostos avaliados obtiveram valores de RMSD de 0,888 a 1,944 Å e energia livre de -6,1 a -9,4 kcal/mol, observando-se ligações de hidrogênio, pontes salinas e pi-enxofre, pi-alquil, e interações hidrofóbicas. Conclusão: Assim, os resultados obtidos mostram o potencial dos compostos analisados frente ao alvo selecionado. Como as simulações computacionais são apenas um passo inicial nos projetos de desenvolvimento de medicamentos antivirais, este estudo fornece dados importantes para pesquisas futuras.

Virtual screening based on molecular docking of lysosomotropic compounds as therapeutic agents for COVID-19 / Triagem virtual baseada no encaixe molecular de compostos lisossomotrópicos como agentes terapêuticos para COVID-19

Objective: Analyze lysosomotropic agents and their action on COVID-19 targets using the molecular docking technique. Methods: Molecular docking analyses of these lysosomotropic agents were performed, namely of fluoxetine, imipramine, chloroquine, verapamil, tamoxifen, amitriptyline, and chlorpromazine against important targets for the pathogenesis of SARS-CoV-2. Results: The results revealed that the inhibitors bind to distinct regions of Mpro COVID-19, with variations in RMSD values from 1.325 to 1.962 Å and binding free energy of -5.2 to -4.3 kcal/mol. Furthermore, the analysis of the second target showed that all inhibitors bonded at the same site as the enzyme, and the interaction resulted in an RMSD variation of 0.735 to 1.562 Å and binding free energy ranging from -6.0 to -8.7 kcal/mol. Conclusion: Therefore, this study allows proposing the use of these lysosomotropic compounds. However, these computer simulations are just an initial step toward conceiving new projects for the development of antiviral molecules.

Objetivo: aAnalisar agentes lisossomotrópicos e sua ação em alvos de COVID-19 usando a técnica de docking molecular. Métodos: Foram realizadas análises de docagem molecular destes agentes lisossomotrópicos, nomeadamente de fluoxetina, imipramina, cloroquina, verapamil, tamoxifeno, amitriptilina e clorpromazina contra alvos importantes para a patogenia do SARS-CoV-2. Resultados: Os resultados revelaram que os inibidores se ligam a regiões distintas do Mpro COVID-19, com variações nos valores de RMSD de 1.325 a 1.962 Å e energia livre de ligação de -5,2 a -4,3 kcal/mol. Além disso, a análise do segundo alvo mostrou que todos os inibidores se ligaram no mesmo sítio da enzima, e a interação resultante em uma variação de RMSD de 0,735 a 1.562 Å e energia livre de ligação variando de -6,0 a -8,7 kcal/mol. Conclusão: Portanto, este estudo permite propor o uso desses compostos lisossomotrópicos. No entanto, essas simulações em computador são apenas um passo inicial para a concepção de novos projetos para o desenvolvimento de moléculas antivirais.

Protective Effect of Quercetin on Renal Tubular Cells and the Involvement with the Renin-Angiotensin-Aldosterone Axis

Abstract Ischemia-reperfusion (I/R) plays an important role in the process of acute kidney injury (AKI) due to the generation of reactive oxygen species (ROS). Substances of natural origin have been studied in the prevention of oxidative damage related to I/R. Quercetin is a flavonoid with antioxidant potential and modulate enzymes, such the inhibition of the Rennin-Angiotensin System (RAS). The aim of this study is to evaluate the nephroprotective effect of quercetin against the I/R and analyze the inhibition of RAS. Rhesus monkey Kidney Epithelial Cells (LLC-MK2 line) were submitted to an in vitro ischemia/reperfusion model. After the reperfusion cells were treated with quercetin, the cell viability was accessed by the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. Tubular cell damage was assessed by the Kidney Injury Molecule-1 (KIM-1) measurement. Oxidative stress was evaluated through Thiobarbituric Acid Reactive Substances (TBARS) and reduced glutathione (GSH). The evaluation of cell death and the mitochondrial depolarization were analyzed by flow cytometry. Quercetin prevents cell death reducing oxidative stress and preventing mitochondrial membrane depolarization. Molecular docking showed that quercetin prevents cell damage better than losartan and lisinopril, inhibitors of RAS. Quercetin has a potential to interact with type 1 angiotensin II receptor (AT1) with greater affinity through the formation of five hydrogen bonds of strong intensity.