When an epidemic started in the Chinese city of Wuhan in December 2019, coronavirus was identified as the cause. Infection by the virus occurs through the interaction of viral S protein with the ...hosts' angiotensin-converting enzyme 2. By leveraging resources such as the DrugBank database and bioinformatics techniques, ligands with potential activity against the SARS-CoV-2 spike protein were designed and identified in this investigation. The FTMap server and the Molegro software were used to determine the active site of the Spike-ACE2 protein's crystal structure. Virtual screening was performed using a pharmacophore model obtained from antiparasitic drugs, obtaining 2000 molecules from molport
. The ADME/Tox profiles were used to identify the most promising compounds with desirable drug characteristics. The binding affinity investigation was then conducted with selected candidates. A molecular docking study showed five structures with better binding affinity than hydroxychloroquine. Ligand_003 showed a binding affinity of -8.645 kcal·mol
, which was considered an optimal value for the study. The values presented by ligand_033, ligand_013, ligand_044, and ligand_080 meet the profile of novel drugs. To choose compounds with favorable potential for synthesis, synthetic accessibility studies and similarity analyses were carried out. Molecular dynamics and theoretical IC
values (ranging from 0.459 to 2.371 µM) demonstrate that these candidates are promising for further tests. Chemical descriptors showed that the candidates had strong molecule stability. Theoretical analyses here show that these molecules have potential as SARS-CoV-2 antivirals and therefore warrant further investigation.
This study investigated the potential of selected compounds as inhibitors of SARS-CoV-2 Mpro through pharmacokinetic and toxicological analyses, molecular docking, and molecular dynamics simulations. ...In silico molecular docking simulations revealed promising ligands with favorable binding affinities for Mpro, ranging from −6.2 to −9.5 kcal/mol. Moreover, molecular dynamics simulations demonstrated the stability of protein–ligand complexes over 200 ns, maintaining protein secondary structures. MM-PBSA analysis revealed favorable interactions between ligands and Mpro, with negative binding energy values. Hydrogen bond formation capacity during molecular dynamics was confirmed, indicating consistent interactions with Mpro catalytic residues. Based on these findings, selected ligands show promise for future studies in developing COVID-19 treatments.
Aedes aegypti mosquitoes transmit several human pathogens that cause millions of deaths worldwide, mainly in Latin America. The indiscriminate use of insecticides has resulted in the development of ...species resistance to some such compounds. Piperidine, a natural alkaloid isolated from Piper nigrum, has been used as a hit compound due to its larvicidal activity against Aedes aegypti. In the present study, piperidine derivatives were studied through in silico methods: pharmacophoric evaluation (PharmaGist), pharmacophoric virtual screening (Pharmit), ADME/Tox prediction (Preadmet/Derek 10.0®), docking calculations (AutoDock 4.2) and molecular dynamics (MD) simulation on GROMACS-5.1.4. MP-416 and MP-073 molecules exhibiting ΔG binding (MMPBSA −265.95 ± 1.32 kJ/mol and −124.412 ± 1.08 kJ/mol, respectively) and comparable to holo (ΔG binding = −216.21 ± 0.97) and pyriproxyfen (a well-known larvicidal, ΔG binding= −435.95 ± 2.06 kJ/mol). Considering future in vivo assays, we elaborated the theoretical synthetic route and made predictions of the synthetic accessibility (SA) (SwissADME), lipophilicity and water solubility (SwissADME) of the promising compounds identified in the present study. Our in silico results show that MP-416 and MP-073 molecules could be potent insecticides against the Aedes aegypti mosquitoes.
To investigate the SARS-CoV-2 Spike protein (Spk)-induced inflammatory response and its downmodulation by diminazene aceturate (DIZE).
Through inducing Spk inflammation in murine models, leukocyte ...migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction.
Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as β2 integrin, PI3K, and PAD2 due to its intermolecular coupling.
Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.
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•SARS-CoV-2 Spike protein (Spk) induces acute inflammatory responses in a murine model of peritonitis.•Diminazene aceturate (DIZE) exerts anti-inflammatory effects on Spk-induced inflammation in mice.•DIZE mitigates DNA extracellular traps (DETs) in human leukocytes: neutrophils, monocytes, and macrophages.
Skin Cancer (SC) is among the most common type of cancers worldwide. The search for SC therapeutics using molecular modeling strategies as well as considering natural plant-derived products seems to ...be a promising strategy. The phytochemical Rocaglamide A (Roc-A) and its derivatives rise as an interesting set of reference compounds due to their
in vitro
cytotoxic activity with SC cell lines. In view of this, we performed a hierarchical virtual screening study considering Roc-A and its derivatives, with the aim to find new chemical entities with potential activity against SC. For this, we selected 15 molecules (Roc-A and 14 derivatives) and initially used them in docking studies to predict their interactions with Checkpoint kinase 1 (Chk1) as a target for SC. This allowed us to compile and use them as a training set to build robust pharmacophore models, validated by Pearson’s correlation (
p
) values and hierarchical cluster analysis (HCA), subsequentially submitted to prospective virtual screening using the Molport
®
database. Outputted compounds were then selected considering their similarities to Roc-A, followed by analyses of predicted toxicity and pharmacokinetic properties as well as of consensus molecular docking using three software. 10 promising compounds were selected and analyzed in terms of their properties and structural features and, also, considering their previous reports in literature. In this way, the 10 promising virtual hits found in this work may represent potential anti-SC agents and further investigations concerning their biological tests shall be conducted.
Rheumatoid Arthritis (RA) is the second most common type of arthritis with symptoms first appearing in patients between 40 and 60 years of age. The number of older persons is projected to double to ...1.5 billion in 2050, globally. Peptidylarginine deiminase Type 4 (PAD4), which catalyzes the conversion of peptidyl-arginine to peptidyl-citrulline, is widely believed to play a causative role in RA disease. Nonsteroidal anti-inflammatories (NSAIDs) and corticosteroids encompass a large group of clinically effective compounds whose mode of action is well established, these compounds relieve pain and reduce inflammation by preventing prostaglandin synthesis through inhibition of cyclooxygenase 2 and the production of arachidonic acid, respectively. We developed a computational protocol/pipeline, using virtual screening approaches to search for new chemical agents (NCA), capable of inhibiting the action of PAD4, in potential, in view of the treatment of RA. Our results allowed the selection of structures with suitable indices of pharmacokinetic properties and estimated low toxicological, in potential, important evidence for selection of more promising molecular candidates against the studied disease. Molecules ZINC20452582 and ZINC67673633 presented better results, as well as the drug-receptor interactions were similar to those observed between the crystallographic compound (GSK147) here used. They presented excellent results for predictions of metabolites, and they can be indicated as promising molecules, resulting from virtual screening approaches, as new PAD4 receptor inhibitors with activity against RA, in potential.
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A series of drugs was investigated to determine structural, electronic and pharmacological properties, as well as the molecular affinity for the main protease of severe acute respiratory syndrome ...coronavirus 2 (SARS‑CoV‑2). The drugs were submitted to density functional theory calculations to optimize structures and predict binding preferences. The optimized geometries were used in molecular docking simulations. In the docking study, the receiver was considered rigid and the drugs flexible. The Lamarckian genetic algorithm with global search and Pseudo-Solis and Wets with local search were adopted for docking. Absorption, distribution, metabolism, excretion and toxicological properties were obtained from the Pre-ADMET online server. In this series, the antiviral atazanavir showed the potential to inhibit the main protease of SARS‑CoV‑2, based on the free binding energy, inhibition constant, binding interactions and its favorable pharmacological properties. Therefore, we recommend carrying out further studies with in vitro tests and subsequent clinical tests to analyze its effectiveness in the treatment of SARS‑CoV‑2.
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•CPW is a polysaccharide fraction from the biomass of Campomanesia adamantium and Campomanesia pubescens.•CPW ameliorates acute and chronic ulcerative colitis.•CPW controls oxidative ...stress and inflammation, protects the mucosal barrier and reduces visceral mechanical hypersensitivity.•CPW is not absorbed from the gut, does not inhibit cytochrome P450 proteins, and does not exhibit AMES toxicity.•CPW is a potential alternative for the relief of ulcerative colitis.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of the gastrointestinal tract. The etiology is not fully understood, but environmental, microbial, and immunologic factors, as well as a genetic predisposition, play a role. UC is characterized by episodes of abdominal pain, diarrhea, bloody stools, weight loss, severe colonic inflammation, and ulceration. Despite the increase in the frequency of UC and the deterioration of the quality of life, there are still patients who do not respond well to available treatment options. Against this background, natural products such as polysaccharides are becoming increasingly important as they protect the intestinal mucosa, promote wound healing, relieve inflammation and pain, and restore intestinal motility. In this study, we investigated the effect of a polysaccharide isolated from the biomass of Campomanesia adamantium and Campomanesia pubescens (here referred to as CPW) in an experimental model of acute and chronic ulcerative colitis induced by dextran sulfate sodium (DSS). CPW reversed weight loss, increased disease activity index (DAI), bloody diarrhea, and colon shortening. In addition, CPW reduced visceral mechanical hypersensitivity, controlled oxidative stress and inflammation, and protected the mucosal barrier. CPW is not absorbed in the intestine, does not inhibit cytochrome P450 proteins, and does not exhibit AMES toxicity. These results suggest that CPW attenuates DSS-induced acute and chronic colitis in mice and may be a potential alternative treatment for UC.
This research aimed to obtain a hematological and biochemical profile of buffalos (
Bubalus bubalis
) bred in a region of the Brazilian Legal Amazon. A total of 73 animals of mixed races, divided ...into three groups, were studied: group 1 (G1) comprised animals up to 11 months old; in group 2 (G2), subjects were 12 to 23 months old; and, in group 3 (G3), they were 24 months old and older. We performed the hematological analysis manually, and, for the biochemistry, we used biochemical analyzers. Age of the animals has influenced the monocyte count. The counting of these cells was higher (
p
> 0.05) in younger animals (G1). There was no difference (
p
> 0.05) in hematological parameters concerning sex. In regard to biochemistry, we found that age influenced results for albumin and urea. Animals from G1 had higher albumin values when compared to G2 and G3. Serum urea values were higher in animals from G3. Regarding the serum mineral parameters, there were no significant results when the different age groups and both sexes were compared. Thus, the hematological and biochemical values obtained can work as a reference for the bubaline species of animals bred in the studied region, under the same management and breeding conditions. Sex and age of the animals are necessary for the interpretation of the tests.
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