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Fridericia chica is widely distributed in Brazil, where it is commonly known as crajiru or pariri in several regions. Despite its popular use for treating inflammations and as an insect repellent, there has been limited assessment of its chemical and biological properties, including its bioinsecticide activities. In this study, we conducted phytochemical analyses and investigated the larvicidal and repellent effects of F. chica against the mosquito Aedes aegypti. The F. chica (HEFc) hydroalcoholic extract was partitioned using column chromatography, and subfractions were analyzed using chromatographic and spectroscopic analyses (ESI-IT-MSn and NMR). In addition, HEFc was evaluated for its larvicidal and repellent activities. Phytochemical analyses revealed the presence of 17 constituents, including 2,4-dihydroxybenzoic and p-coumaric acids, along with umbelliferone, acetovanilone, myricetin-3-O-glucuronide, and cis-isorhapontigenin, which are reported for the first time in this species. Although no larvicidal effect was observed at the doses tested, the HEFc exhibited promising repellent effects against A. aegypti, which aligns with its ethnopharmacological potential. In addition, molecular docking studies demonstrated that the compounds of HEFc interacted efficiently with insect odorant binding proteins (OBPs), providing repellent effects. Consistent with the chemical profile and in silico studies, preparations of F. chica have considerable repellent potential.
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Two new caffeoyl triterpenes, cis-lupacosmeol (1) alone and in mixture with trans-lupacosmeol (2), and two known compounds, 16ß-hydroxy-3ß-trans-caffeoyl-olean-12-ene (3) and 16ß-hydroxy-3ß-p-coumaroyl-lup-20(29)-ene (4), were isolated from the roots of Acosmium diffusissimum. The structures were chemically characterised using 1D and 2D NMR, IR spectroscopy, and HRESIMS techniques. Cytotoxicity was evaluated against three different cancer cell lines (MCF-7, HCT-116, SK-MEL-28). Only mixture 2 showed activity against all strains tested, with more pronounced ability to inhibit SK-MEL-28 growth (IC50: 25.45 µg/mL). Molecular docking studies suggested that the cytotoxic activity of 2 was strongly attributed to interactions between cis-lupacosmeol and trans-lupacosmeol, which are present in mixtures used to treat melanoma and exhibit activities towards different molecular targets of importance.
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Acute myeloid leukemia (AML) is the most common hematological cancer in the adult population worldwide. Approximately 35% of patients with AML present internal tandem duplication (ITD) mutations in the FMSlike tyrosine kinase 3 (FLT3) receptor associated with poor prognosis, and thus, this receptor is a relevant target for potential therapeutics. Tyrosine kinase inhibitors (TKIs) are used to treat AML; however, their molecular interactions and effects on leukemic cells are poorly understood. The present study aimed to gain insights into the molecular interactions and affinity forces of four TKI drugs (sorafenib, midostaurin, gilteritinib and quizartinib) with the wildtype (WT)FLT3 and ITDmutated (ITDFLT3) structural models of FLT3, in its inactive aspartic acidphenylalanineglycine motif (DFGout) and active aspartic acidphenylalanineglycine motif (DFGin) conformations. Furthermore, the present study evaluated the effects of the secondgeneration TKIs gilteritinib and quizartinib on cancer cell viability, apoptosis and proliferation in the MV411 (ITDFLT3) and HL60 (WTFLT3) AML cell lines. Peripheral blood mononuclear cells (PBMCs) from a healthy volunteer were included as an FLT3negative group. Molecular docking analysis indicated higher affinities of secondgeneration TKIs for WTFLT3/DFGout and WTFLT3/DFGin compared with those of the firstgeneration TKIs. However, the ITD mutation changed the affinity of all TKIs. The in vitro data supported the in silico predictions: MV411 cells presented high selective sensibility to gilteritinib and quizartinib compared with the HL60 cells, whereas the drugs had no effect on PBMCs. Thus, the current study presented novel information about molecular interactions between the FLT3 receptors (WT or ITDmutated) and some of their inhibitors. It also paves the way for the search for novel inhibitory molecules with potential use against AML.
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Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Estaurosporina , Tirosina Quinase 3 Semelhante a fms , Humanos , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzotiazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Tirosina Quinase 3 Semelhante a fms/química , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Simulação de Acoplamento Molecular , Mutação , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Sorafenibe/farmacologia , Estaurosporina/análogos & derivados , Estaurosporina/farmacologia , Triazinas/farmacologia , Triazinas/químicaRESUMO
Background: The ability to predict and comprehend molecular interactions offers significant insights into the biological functions of proteins. The interaction between surface protein 47 of Plasmodium falciparum (Pfs47) and receptor of the protein 47 (P47Rec) has attracted increased attention due to their role in parasite evasion of the mosquito immune system and the concept of geographical coevolution between species. The aims of this study were as follows: to apply a bioinformatics approach to investigate the interaction between Pfs47 and P47Rec proteins and to identify the potential binding sites, protein orientations and receptor specificity sites concerning the geographical origins of the vectors and the parasite. Methods: Public sequences of the pfs47 and p47rec genes were downloaded and subsequently filtered to predict functional and structural annotations of the Pfs47-P47Rec complex. Phylogenetic analyses of both proteins were carried out. In addition, the p47Rec gene was subjected to sequencing and subsequent analysis in 2 distinct Anopheles species collected in Honduras. Results: The examination of motifs reveals a significant degree of conservation in pfs47, suggesting that Pfs47 might have undergone recent evolutionary development and adaptation. Structural models and docking analyses supported the theory of selectivity of Plasmodium falciparum strains towards their vectors in diverse geographical regions. A detailed description of the putative interaction between the Pfs47-P47Rec complex is shown. Conclusions: The study identifies coevolutionary patterns between P47Rec and Pfs47 related to the speciation and geographic dispersion of Anopheles species and Plasmodium falciparum, with Pfs47 evolving more recently than P47Rec. This suggests a link between the parasite's adaptability and existing anopheline species across different regions. P47Rec likely has a cytoplasmic localization due to its lack of membrane attachment elements. However, these findings are based on simulations and require validation through methods like cryo-electron microscopy. A significant limitation is the scarcity of sequences in global databases, which restricts precise interaction modelling. Further research with diverse parasite isolates and anopheline species is recommended to enhance understanding of these proteins' structure and interaction.
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Visceral leishmaniasis (VL), caused by protozoa of the genus Leishmania, remains a significant public health concern due to its potentially lethal nature if untreated. Current chemotherapy options are limited by severe toxicity and drug resistance. Derivatives of 1,2,4-oxadiazole have emerged as promising drug candidates due to their broad biological activity. This study investigated the effects of novel 1,2,4-oxadiazole derivatives (Ox1-Ox7) on Leishmania infantum, the etiological agent of VL. In silico predictions using SwissADME suggest that these compounds have high oral absorption and good bioavailability. Among them, Ox1 showed the most promise, with higher selectivity against promastigotes and lower cytotoxicity towards L929 fibroblasts and J774.G8 macrophages. Ox1 exhibited selectivity indices of 18.7 and 61.7 against L. infantum promastigotes and amastigotes, respectively, compared to peritoneal macrophages. Ultrastructural analyses revealed severe morphological damage in both parasite forms, leading to cell death. Additionally, Ox1 decreased the mitochondrial membrane potential in promastigotes, as shown by flow cytometry. Molecular docking and dynamic simulations indicated a strong affinity of Ox1 for the L. infantum CYP51 enzyme. Overall, Ox1 is a promising and effective compound against L. infantum.
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Antiprotozoários , Leishmania infantum , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oxidiazóis , Proteínas de Protozoários , Leishmania infantum/efeitos dos fármacos , Oxidiazóis/química , Oxidiazóis/farmacologia , Antiprotozoários/farmacologia , Antiprotozoários/química , Animais , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/química , Camundongos , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Linhagem Celular , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
Anthocyanins are bioactive compounds responsible for various physiological processes in plants and provide characteristic colors to fruits and flowers. Their biosynthetic pathway is well understood; however, the enzymatic degradation mechanism is less explored. Anthocyanase (ß-glucosidase (BGL)), peroxidase (POD), and polyphenol oxidase (PPO) are enzymes involved in degrading anthocyanins in plants such as petunias, eggplants, and Sicilian oranges. The aim of this work was to investigate the physicochemical interactions between these enzymes and the identified anthocyanins (via UPLC-MS/MS) in cranberry (Vaccinium macrocarpon) through molecular docking to identify the residues likely involved in anthocyanin degradation. Three-dimensional models were constructed using the AlphaFold2 server based on consensus sequences specific to each enzyme. The models with the highest confidence scores (pLDDT) were selected, with BGL, POD, and PPO achieving scores of 87.6, 94.8, and 84.1, respectively. These models were then refined using molecular dynamics for 100 ns. Additionally, UPLC-MS/MS analysis identified various flavonoids in cranberries, including cyanidin, delphinidin, procyanidin B2 and B4, petunidin, pelargonidin, peonidin, and malvidin, providing important experimental data to support the study. Molecular docking simulations revealed the most stable interactions between anthocyanase and the anthocyanins cyanidin 3-arabinoside and cyanidin 3-glucoside, with a favorable ΔG of interaction between -9.3 and -9.2 kcal/mol. This study contributes to proposing a degradation mechanism and seeking inhibitors to prevent fruit discoloration.
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Antocianinas , Catecol Oxidase , Simulação de Acoplamento Molecular , Vaccinium macrocarpon , Antocianinas/química , Antocianinas/metabolismo , Catecol Oxidase/metabolismo , Catecol Oxidase/química , Vaccinium macrocarpon/química , Peroxidase/metabolismo , Peroxidase/química , Espectrometria de Massas em Tandem , Proteínas de Plantas/metabolismo , Proteínas de Plantas/química , Simulação de Dinâmica Molecular , Simulação por Computador , Frutas/química , Frutas/metabolismo , Frutas/enzimologiaRESUMO
Several natural products are being studied to identify new bioactive molecules with therapeutic potential for infections, immune modulation, and other pathologies. TLRs are a family of receptors that play a crucial role in the immune system, constituting the first line of immune defense. They recognize specific products derived from microorganisms that activate multiple pathways and transcription factors in target cells, which are vital for producing immune mediators. Mygalin is a synthetic acylpolyamine derived from hemocytes of the spider Acanthoscurria gomesiana. This molecule negatively regulates macrophage response to LPS stimulation by interacting with MD2 in the TLR4/MD2 complex. Here, we investigated the activity of Mygalin mediated by TLR2 agonists in cells treated with Pam3CSK4 (TLR2/1), Pam2CSK4, Zymosan (TLR2/6), and IFN-γ. Our data showed that Mygalin significantly inhibited stimulation with agonists and IFN-γ, reducing NO and IL-6 synthesis, regardless of the stimulation. There was also a significant reduction in the phosphorylation of proteins NF-κB p65 and STAT-1 in cells treated with Pam3CSK4. Molecular docking assays determined the molecular structure of Mygalin and agonists Pam3CSK4, Pam2CSK4, and Zymosan, as well as their interaction and free energy with the heterodimeric complexes TLR2/1 and TLR2/6. Mygalin interacted with the TLR1 and TLR2 dimer pathway through direct interaction with the agonists, and the ligand-binding domain was similar in both complexes. However, the binding of Mygalin was different from that of the agonists, since the interaction energy with the receptors was lower than with the agonists for their receptors. In conclusion, this study showed the great potential of Mygalin as a potent natural inhibitor of TLR2/1 and TLR2/6 and a suppressor of the inflammatory response induced by TLR2 agonists, in part due to its ability to interact with the heterodimeric complexes.
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Interferon gama , Receptor 2 Toll-Like , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/metabolismo , Animais , Interferon gama/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopeptídeos/farmacologia , Células RAW 264.7 , Humanos , Transdução de Sinais/efeitos dos fármacos , Zimosan/farmacologia , Interleucina-6/metabolismo , Polissacarídeos/farmacologia , Polissacarídeos/química , Fator de Transcrição RelA/metabolismoRESUMO
Aim: This work aimed to synthesize a new pyrimidine PYB01 with potential application against antimicrobial resistance.Materials & methods: PYB01 was synthesized through condensation reaction between 3a and 3b. The antimicrobial evaluation was carried out using the microdilution method in Mueller-Hinton Agar and in silico predictions using different software.Results: PYB01 has moderate antibiotic activity and high capacity to efficiently modulate antibiotic resistance in Staphylococcus aureus. In silico evaluations demonstrated that PYB01 is probably an allosteric inhibitor of Protein Binding Penicilin 2a and modulates the action of oxacillin by decreasing the minimum inhibitory concentration by 64-times. PYB01 demonstrate a good pharmacokinetic profile and toxicological.Conclusion: PYB01 has great potential to go further in investigating its use against antimicrobial resistance.
[Box: see text].
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Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Oxacilina , Pirimidinas , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Oxacilina/farmacologia , Estrutura Molecular , Sinergismo Farmacológico , Animais , HumanosRESUMO
The widely used insecticide chlorpyrifos (CP) is known to inhibit acetylcholinesterase (AChE) activity attributed to result in various neurological disorders and acetylcholine-dependent organ functions including heart, skeletal muscle, lung, gastrointestinal tract, and central nervous systems. Enzyme reactivators, such as oximes, are known to restore AChE activity and mitigate adverse effects. The identification of compounds that reactivate AChE constitute agents with important therapeutic beneficial effects in cases of pesticide poisoning. However, the screening of novel drugs using traditional models may raise ethical concerns. This study aimed to investigate the potential of Drosophila melanogaster as a model organism for screening AChE reactivators, with a focus on organophosphate poisoning. The efficacy of several oximes, including pralidoxime, trimedoxime, obidoxime, methoxime, HI-6, K027, and K048, against CP-induced AChE activity inhibition in D. melanogaster was determined in silico, in vitro, and in vivo experiments. Molecular docking studies indicated a strong interaction between studied oximes and the active-site gorge of AChE. Data showed that selected oximes (100 µM) are effective in the reactivation of AChE inhibited by CP (10 µM) in vitro. Finally, in vivo investigations demonstrated that selected oximes, pralidoxime and K048 (1.5 ppm), reversed the locomotor deficits, inhibition of AChE activity as well as lowered the mortality rates induced by CP (0.75 ppm). Our findings contribute to utilization of D. melanogaster as a robust model for determination of actions of identified new AChE inhibitory agents with more effective therapeutic properties that those currently in use in the clinical practice in treatment of AChE associated disorders.
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Acetilcolinesterase , Clorpirifos , Reativadores da Colinesterase , Drosophila melanogaster , Simulação de Acoplamento Molecular , Oximas , Animais , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/enzimologia , Reativadores da Colinesterase/farmacologia , Clorpirifos/toxicidade , Acetilcolinesterase/metabolismo , Oximas/farmacologia , Modelos Animais , Inseticidas/toxicidade , Inibidores da Colinesterase/toxicidadeRESUMO
The Target-Based Virtual Screening approach is widely employed in drug development, with docking or molecular dynamics techniques commonly utilized for this purpose. This systematic review (SR) aimed to identify in silico therapeutic targets for treating Diabetes mellitus (DM) and answer the question: What therapeutic targets have been used in in silico analyses for the treatment of DM? The SR was developed following the guidelines of the Preferred Reporting Items Checklist for Systematic Review and Meta-Analysis, in accordance with the protocol registered in PROSPERO (CRD42022353808). Studies that met the PECo strategy (Problem, Exposure, Context) were included using the following databases: Medline (PubMed), Web of Science, Scopus, Embase, ScienceDirect, and Virtual Health Library. A total of 20 articles were included, which not only identified therapeutic targets in silico but also conducted in vivo analyses to validate the obtained results. The therapeutic targets most frequently indicated in in silico studies were GLUT4, DPP-IV, and PPARγ. In conclusion, a diversity of targets for the treatment of DM was verified through both in silico and in vivo reassessment. This contributes to the discovery of potential new allies for the treatment of DM.
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Simulação por Computador , Diabetes Mellitus , Suplementos Nutricionais , Hipoglicemiantes , Humanos , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Animais , Desenvolvimento de Medicamentos/métodos , PPAR gama/metabolismo , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular/métodosRESUMO
Bioinformatics has emerged as a valuable tool for screening drugs and understanding their effects. This systematic review aimed to evaluate whether in silico studies using anti-obesity peptides targeting therapeutic pathways for obesity, when subsequently evaluated in vitro and in vivo, demonstrated effects consistent with those predicted in the computational analysis. The review was framed by the question: "What peptides or proteins have been used to treat obesity in in silico studies?" and structured according to the acronym PECo. The systematic review protocol was developed and registered in PROSPERO (CRD42022355540) in accordance with the PRISMA-P, and all stages of the review adhered to these guidelines. Studies were sourced from the following databases: PubMed, ScienceDirect, Scopus, Web of Science, Virtual Heath Library, and EMBASE. The search strategies resulted in 1015 articles, of which, based on the exclusion and inclusion criteria, 7 were included in this systematic review. The anti-obesity peptides identified originated from various sources including bovine alpha-lactalbumin from cocoa seed (Theobroma cacao L.), chia seed (Salvia hispanica L.), rice bran (Oryza sativa), sesame (Sesamum indicum L.), sea buckthorn seed flour (Hippophae rhamnoides), and adzuki beans (Vigna angularis). All articles underwent in vitro and in vivo reassessment and used molecular docking methodology in their in silico studies. Among the studies included in the review, 46.15% were classified as having an "uncertain risk of bias" in six of the thirteen criteria evaluated. The primary target investigated was pancreatic lipase (n = 5), with all peptides targeting this enzyme demonstrating inhibition, a finding supported both in vitro and in vivo. Additionally, other peptides were identified as PPARγ and PPARα agonists (n = 2). Notably, all peptides exhibited different mechanisms of action in lipid metabolism and adipogenesis. The findings of this systematic review underscore the effectiveness of computational simulation as a screening tool, providing crucial insights and guiding in vitro and in vivo investigations for the discovery of novel anti-obesity peptides.
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Simulação por Computador , Obesidade , Peptídeos , Animais , Humanos , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Biologia Computacional , Simulação de Acoplamento Molecular , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Peptídeos/química , Peptídeos/farmacologiaRESUMO
Visceral cestodiases, like cysticercoses and echinococcoses, are caused by cystic larvae from parasites of the Cestoda class and are endemic or hyperendemic in many areas of the world. Current therapeutic approaches for these diseases are complex and present limitations and risks. Therefore, new safer and more effective treatments are urgently needed. The Niemann-Pick C1 (NPC1) protein is a cholesterol transporter that, based on genomic data, would be the solely responsible for cholesterol uptake in cestodes. Considering that human NPC1L1 is a known target of ezetimibe, used in the treatment of hypercholesterolemia, it has the potential for repurposing for the treatment of visceral cestodiases. Here, phylogenetic, selective pressure and structural in silico analyses were carried out to assess NPC1 evolutive and structural conservation, especially between cestode and human orthologs. Two NPC1 orthologs were identified in cestode species (NPC1A and NPC1B), which likely underwent functional divergence, leading to the loss of cholesterol transport capacity in NPC1A. Comparative interaction analyses performed by molecular docking of ezetimibe with human NPC1L1 and cestode NPC1B pointed out to similarities that consolidate the idea of cestode NPC1B as a target for the repurposing of ezetimibe as a drug for the treatment of visceral cestodiases.
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Cestoides , Ezetimiba , Proteína C1 de Niemann-Pick , Ezetimiba/farmacologia , Ezetimiba/uso terapêutico , Humanos , Animais , Proteína C1 de Niemann-Pick/metabolismo , Cestoides/metabolismo , Cestoides/efeitos dos fármacos , Cestoides/genética , Filogenia , Simulação de Acoplamento Molecular , Reposicionamento de Medicamentos/métodos , Simulação por Computador , Colesterol/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/química , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêuticoRESUMO
CONTEXT: Drosophila suzukii (Matsumura, 1931) is a widespread agricultural pest responsible for significant damage to various soft-skinned fruit hosts. The revolutionary potential of bioinformatics in agriculture emerges from its ability to provide extensive information on pests, fungi, chemical resistance, implications of non-target species, and other critical aspects. This wealth of information allows researchers to engage in projects and applied research in diverse agricultural domains that face these challenges. In this context, bioinformatics tools play a fundamental role. The negative impact of pests on crops, resulting in substantial economic losses, has highlighted the importance of in silico methods. METHODS: To achieve this, we conducted a systematic search in scientific databases using as keywords "Drosophila suzukii," "biopesticides," "simulations computational," and "in-silico." After applying the filters of relevance and publication date, we organized the articles and prioritized those that directly addressed that matched the keywords and the use of bioinformatics tools. Additionally, we included studies focusing on in silico assays of biopesticides, such as molecular docking. Our review aimed to present a collection of recent literature on biopesticides against Drosophila suzukii, emphasizing bioinformatics methods. Through this work, we strive to contribute to the literature of new perspectives on the development and efficiency of biopesticides, along with to advance research that may improve pest control strategies. RESULTS: In the results of the systematic review, we found 2734 articles related to the selected keywords. Six of these articles directly address Drosophila suzukii and the use of bioinformatics tools in the search for alternatives in pest control. In the selected studies, we observed that two articles tend to focus on phylogenetic approaches, searching for gene sequences, amino acids, and constructing phylogenetic trees. The other three articles used molecular modeling and docking of receptors such as GABA and TRP with plant-derived and synthetic compounds to study intermolecular interactions. However, we identified gaps in these studies that could lead to further research in the biorational development of biopesticides using bioinformatics tools.
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Drosophila , Inseticidas , Animais , Biologia Computacional/métodos , Drosophila/efeitos dos fármacos , Inseticidas/química , Inseticidas/farmacologia , Simulação de Acoplamento Molecular , Praguicidas/química , Praguicidas/farmacologiaRESUMO
INTRODUCTION: Candida auris is a globally disseminated invasive ascomycetous yeast, that imposes a substantial burden on healthcare systems. It has been documented to have spread to over 40 countries across six continents, necessitating in-depth comprehension through advanced techniques like Whole-Genome Sequencing. METHOD: This study entailed the isolation and Whole-Genome Sequencing of a fluconazole-resistant C. auris strain (CA01) obtained from a patient's blood in Beijing. Genome analysis was conducted to classify the strain, and molecular docking was performed to understand the impact of mutations on drug resistance. RESULTS: Genome analysis revealed that CA01 belongs to the South Asia Clade (I) and shares the closest genetic relationship with previously reported strains BJCA001 and BJCA002. Notably, unlike BJCA001, CA01 exhibits significant resistance to fluconazole primarily due to the A395T mutation in the ERG11 gene. Molecular docking studies demonstrated that this mutation leads to geometric changes in the active site where fluconazole binds, resulting in decreased binding affinity. Additionally, the present findings have identified several core virulence genes in C. auris, such as RBF1. DISCUSSION: The findings from this study expand the understanding of the genetic diversity and adaptive mechanisms of C. auris within the South Asia Clade (I). The observed fluconazole resistance driven by the ERG11 mutation A395T highlights the need for heightened awareness and adaptation in clinical treatment strategies in China. This study provides critical insights into drug resistance and virulence profiles at a genetic level, which could guide future therapeutic and management strategies for C. auris infections.
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Antifúngicos , Candida auris , Farmacorresistência Fúngica , Fluconazol , Humanos , Farmacorresistência Fúngica/genética , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Virulência/genética , Candida auris/genética , Candida auris/efeitos dos fármacos , Candida auris/patogenicidade , Testes de Sensibilidade Microbiana , Mutação , Pequim , Simulação de Acoplamento Molecular , Candidíase/microbiologia , Candidíase/tratamento farmacológico , Sequenciamento Completo do Genoma , Ásia MeridionalRESUMO
The DockThor-VS platform (https://dockthor.lncc.br/v2/) is a free protein-ligand docking server conceptualized to facilitate and assist drug discovery projects to perform docking-based virtual screening experiments accurately and using high-performance computing. The DockThor docking engine is a grid-based method designed for flexible-ligand and rigid-receptor docking. It employs a multiple-solution genetic algorithm and the MMFF94S molecular force field scoring function for pose prediction. This engine was engineered to handle highly flexible ligands, such as peptides. Affinity prediction and ranking of protein-ligand complexes are performed with the linear empirical scoring function DockTScore. The main steps of the ligand and protein preparation are available on the DockThor Portal, making it possible to change the protonation states of the amino acid residues, and include cofactors as rigid entities. The user can also customize and visualize the main parameters of the grid box. The results of docking experiments are automatically clustered and ordered, providing users with a diverse array of meaningful binding modes. The platform DockThor-VS offers a user-friendly interface and powerful algorithms, enabling researchers to conduct virtual screening experiments efficiently and accurately. The DockThor Portal utilizes the computational strength of the Brazilian high-performance platform SDumont, further amplifying the efficiency and speed of docking experiments. Additionally, the web server facilitates and enhances virtual screening experiments by offering curated structures of potential targets and compound datasets, such as proteins related to COVID-19 and FDA-approved drugs for repurposing studies. In summary, DockThor-VS is a dynamic and evolving solution for docking-based virtual screening to be applied in drug discovery projects.
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Simulação de Acoplamento Molecular , Software , Ligantes , Algoritmos , Descoberta de Drogas/métodos , Ligação Proteica , Humanos , Proteínas/química , Proteínas/metabolismo , Interface Usuário-ComputadorRESUMO
BACKGROUND: Guettarda viburnoides Cham. & Schltdl., "veludinho do campo", is used in the Brazilian Amazon for its effects on the central nervous system (CNS) as a "brain tonic"; however, scientific evidence is needed to elucidate its ethnobotanical uses. OBJECTIVE: This study evaluated the neurobehavioural effects of an ethanolic extract of G. viburnoides (EEGV). Molecular docking, microchemical and morphoanatomical features of the species were investigated. METHODS: EEGV was investigated by UHPLCâMS/MS and dereplication and molecular network were investigated using platforms available for natural product chemistry. For the in vivo assay, EEGV was administered to mice orally (3, 30 or 100 mg/kg). The effect of EEGV on spatial memory was measured using the Morris water maze test in mice with scopolamine-induced amnesia. The depression- and anxiety-like effects were assessed by forced swimming, tail suspension, marble burying and elevated plus maze tests. The AChE inhibition was evaluated in the brains of treated mice and molecular docking simulations were carried out with the main constituents. The leaves and stems of G. viburnoides were analysed via optical microscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy. RESULTS: Secoxyloganin, grandifloroside, hyperin/or isoquercitrin, uncaric acid and ursolic acid were identified by UHPLCâMS/MS. Molecular networking by three flavonoids, three triterpenes, two coumarins, two iridoids, and one phenolic acid. EEGV reversed these scopolamineinduced effects. In the forced swim and tail suspension test, EEGV (30 and 100 mg/kg) significantly reduced the immobility time. EEGV significantly reduced the number of buried marbles, while in the elevated plus maze test, no changes were observed compared to the Sco group. AChE activity was altered in the hippocampus. Studies of the molecular coupling of iridoid glycosides (grandifloroside and secoxyloganin) and flavonoid hyperin with AChE revealed significant interactions, corroborating the activity indicated by the inhibition assay. CONCLUSIONS: These results might be in accordance with medicinal use for neuroprotetor effects and important microchemical and micromorphological data that support the identification and quality control of G. viburnoides.
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Leishmaniasis is a group of neglected, vector-borne infectious diseases that affect millions of people around the world. The medications available for its treatment, especially in cases of visceral leishmaniasis, are old, outdated and have serious side effects. In this work, 10 chalcones were synthesised and evaluated in vitro against promastigotes and axenic amastigotes of Leishmania infantum. Compounds CP04 and CP06 were the most promising, respectively presenting IC50 values = 13.64 ± 0.25 and 11.19 ± 0.22 µM against promastigotes, and IC50 = 18.92 ± 0.05 and 22.42 ± 0.05 µM against axenic amastigotes. Only compound CP04 did not show cytotoxicity against peripheral blood mononuclear cells (PBMCs). Molecular docking studies conducted with sterol 14-alpha demethylase (CYP-51) (PDB: 3L4D) and trypanothione reductase (PDB: 5EBK) enzymes from L. infantum evidenced the great affinity of compound CP04 for these targets, presenting Moldock score values of -94.0758 and -50.5692 KJ/mol-1.
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This work describes the evaluation the potentiating activity of antibiotics by campesterol (1) and its derivatives (2-11) against multiresistant strains of Staphylococcusaureus 10, Escherichia coli 06 and Pseudomonas aeruginosa 24 employing the microdilution test. When subjected to the in vitro potentiating activity bioassay, all compounds showed a potentiating effect associated with norfloxacin against E. coli and P. aeruginosa with a reduction in the MIC of the antibiotic of up to 75%. These compounds also reduced the MIC of gentamicin by 37% to 87% in S. aureus and E. coli. Additionally, molecular docking studies were conducted to gain a deeper understanding of the interactions between the appropriate proteins and the most effective compounds (2, 4, 9, and 10 against E. coli; 1, 2, 3, 5, 8, and 9 against S. aureus), including antibiotics. This paper registers for the first time the in vitro and in silico studies on the action of compounds 1-11 in antibiotic potentiation.
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A differential diet with royal jelly (RJ) during early larval development in honeybees shapes the phenotype, which is probably mediated by epigenetic regulation of gene expression. Evidence indicates that small molecules in RJ can modulate gene expression in mammalian cells, such as the fatty acid 10-hydroxy-2-decenoic acid (10-HDA), previously associated with the inhibition of histone deacetylase enzymes (HDACs). Therefore, we combined computational (molecular docking simulations) and experimental approaches for the screening of potential HDAC inhibitors (HDACi) among 32 RJ-derived fatty acids. Biochemical assays and gene expression analyses (Reverse Transcriptase - quantitative Polymerase Chain Reaction) were performed to evaluate the functional effects of the major RJ fatty acids, 10-HDA and 10-HDAA (10-hydroxy-decanoic acid), in two human cancer cell lines (HCT116 and MDA-MB-231). The molecular docking simulations indicate that these fatty acids might interact with class I HDACs, specifically with the catalytic domain of human HDAC2, likewise well-known HDAC inhibitors (HDACi) such as SAHA (suberoylanilide hydroxamic acid) and TSA (Trichostatin A). In addition, the combined treatment with 10-HDA and 10-HDAA inhibits the activity of human nuclear HDACs and leads to a slight increase in the expression of HDAC-coding genes in cancer cells. Our findings indicate that royal jelly fatty acids collectively contribute to HDAC inhibition and that 10-HDA and 10-HDAA are weak HDACi that facilitate the acetylation of lysine residues of chromatin, triggering an increase in gene expression levels in cancer cells.
Assuntos
Ácidos Graxos , Inibidores de Histona Desacetilases , Simulação de Acoplamento Molecular , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Ácidos Graxos/metabolismo , Abelhas , Linhagem Celular Tumoral , Animais , Ácidos Graxos Monoinsaturados/farmacologia , Ácidos Graxos Monoinsaturados/química , Histona Desacetilase 2/metabolismo , Histona Desacetilase 2/genética , Histona Desacetilase 2/antagonistas & inibidores , Células HCT116RESUMO
Much work has been dedicated to the quest to determine the structure-activity relationship in synthetic brassinosteroid (BR) analogs. Recently, it has been reported that analogs with phenyl or benzoate groups in the alkyl chain present activities comparable to those shown by natural BRs, depending on the nature of the substituent in the aromatic ring. However, as it is well known that the activity depends on the structure of the whole molecule, in this work, we have synthesized a series of compounds with the same substituted benzoate in the alkyl chain and a hydroxyl group at C3. The main goal was to compare the activities with analogs with -OH at C2 and C3. Additionally, a molecular-docking study and molecular dynamics simulations were performed to establish a correlation between the experimental and theoretical results. The synthesis of eight new BR analogs was described. All the analogs were fully characterized by spectroscopical methods. The bioactivity of these analogs was assessed using the rice lamina inclination test (RLIT) and the inhibition of the root and hypocotyl elongation of Arabidopsis thaliana. The results of the RLIT indicate that at the lowest tested concentration (1 × 10-8 M), in the BR analogs in which the aromatic ring was substituted at the para position with methoxy, the I and CN substituents were more active than brassinolide (50-72%) and 2-3 times more active than those analogs in which the substituent group was F, Cl or Br atoms. However, at the highest concentrations, brassinolide was the most active compound, and the structure-activity relationship changed. On the other hand, the results of the A. thaliana root sensitivity assay show that brassinolide and the analogs with I and CN as substituents on the benzoyl group were the most active compounds. These results are in line with those obtained via the RLIT. A comparison of these results with those obtained for similar analogs that had a hydroxyl group at C2 indicates the importance of considering the whole structure. The molecular-docking results indicate that all the analogs adopted a brassinolide-like orientation, while the stabilizing effect of the benzoate group on the interactions with the receptor complex provided energy binding values ranging between -10.17 and -13.17 kcal mol-1, where the analog with a nitrile group was the compound that achieved better contact with the amino acids present in the active site.