Natural Compound Targeting Research Articles

Recent advances in neuroinflammation prevention and therapy: the role of natural products and underlying mechanisms based on molecular targets.

Neuroinflammation is initiated in response to a variety of endogenous and exogenous sources. As the resident macrophages of the central nervous system, the polarization of microglia into either the M1 pro-inflammatory phenotype or the M2 anti-inflammatory phenotype holds great promise as a therapeutic strategy for neuroinflammation. Natural products, comprising a vital chemical library with distinctive structures and diverse functions, have been extensively employed to modulate microglial polarization for the treatment of neuroinflammation. In this review, we present up-to-date and extensive insights into the therapeutic effects and underlying mechanisms of natural products in the context of neuroinflammation. Furthermore, the review aims to present a new perspective by focusing on the targets of natural compounds, elucidating the molecular mechanisms and guiding the transition from natural-derived lead compounds to potential anti-neuroinflammatory drugs. Additionally, we provide a comprehensive overview of the challenges and limitations associated with the utilization of natural products for neuroinflammation therapy.

Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis.

Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin gene family gene that encodes proteins vital for the growth, maintenance, and survival of neurons in the nervous system. The study aimed to screen natural compounds against BDNF variant (V66M), which affects memory, cognition, and mood regulation. BDNF variant (V66M) as a target structure was selected, and Vitamin D, Curcumin, Vitamin C, and Quercetin as ligands structures were taken from PubChem database. Multiple tools like AUTODOCK VINA, BIOVIA discovery studio, PyMOL, CB-dock, IMOD server, Swiss ADEMT, and Swiss predict ligands target were used to analyze binding energy, interaction, stability, toxicity, and visualize BDNF-ligand complexes. Compounds Vitamin D3, Curcumin, Vitamin C, and Quercetin with binding energies values of - 5.5, - 6.1, - 4.5, and - 6.7 kj/mol, respectively, were selected. The ligands bind to the active sites of the BDNF variant (V66M) via hydrophobic bonds, hydrogen bonds, and electrostatic interactions. Furthermore, ADMET analysis of the ligands revealed they exhibited sound pharmacokinetic and toxicity profiles. In addition, an MD simulation study showed that the most active ligand bound favorably and dynamically to the target protein, and protein-ligand complex stability was determined. The finding of this research could provide an excellent platform for discovering and rationalizing novel drugs against stress related to BDNF (V66M). Docking, preclinical drug testing and MD simulation results suggest Quercetin as a more potent BDNF variant (V66M) inhibitor and forming a more structurally stable complex.

The pharmacological effects of Berberine and its therapeutic potential in different diseases: Role of the phosphatidylinositol 3-kinase/AKT signaling pathway.

The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a central role in cell growth and survival and is disturbed in various pathologies. The PI3K is a kinase that generates phosphatidylinositol-3,4,5-trisphosphate (PI (3-5) P3), as a second messenger responsible for the translocation of AKT to the plasma membrane and its activation. However, due to the crucial role of the PI3K/AKT pathway in regulation of cell survival processes, it has been introduced as a main therapeutic target for natural compounds during the progression of different pathologies. Berberine, a plant-derived isoquinone alkaloid, is known because of its anti-inflammatory, antioxidant, antidiabetic, and antitumor properties. The effect of this natural compound on cell survival processes has been shown to be mediated by modulation of the intracellular pathways. However, the effects of this natural compound on the PI3K/AKT pathway in various pathologies have not been reviewed so far. Therefore, this paper aims to review the PI3K/AKT-mediated effects of Berberine in different types of cancer, diabetes, cardiovascular, and central nervous system diseases.

Pharmacogenomic Analysis of Combined Therapies against Glioblastoma Based on Cell Markers from Single-Cell Sequencing.

Glioblastoma is the most common and aggressive form of primary brain cancer and the lack of viable treatment options has created an urgency to develop novel treatments. Personalized or predictive medicine is still in its infancy stage at present. This research aimed to discover biomarkers to inform disease progression and to develop personalized prophylactic and therapeutic strategies by combining state-of-the-art technologies such as single-cell RNA sequencing, systems pharmacology, and a polypharmacological approach. As predicted in the pyroptosis-related gene (PRG) transcription factor (TF) microRNA (miRNA) regulatory network, TP53 was the hub gene in the pyroptosis process in glioblastoma (GBM). A LASSO Cox regression model of pyroptosis-related genes was built to accurately and conveniently predict the one-, two-, and three-year overall survival rates of GBM patients. The top-scoring five natural compounds were parthenolide, rutin, baeomycesic acid, luteolin, and kaempferol, which have NFKB inhibition, antioxidant, lipoxygenase inhibition, glucosidase inhibition, and estrogen receptor agonism properties, respectively. In contrast, the analysis of the cell-type-specific differential expression-related targets of natural compounds showed that the top five subtype cells targeted by natural compounds were endothelial cells, microglia/macrophages, oligodendrocytes, dendritic cells, and neutrophil cells. The current approach-using the pharmacogenomic analysis of combined therapies-serves as a model for novel personalized therapeutic strategies for GBM treatment.

Computational biology-based study of the molecular mechanism of spermidine amelioration of acute pancreatitis.

Acute pancreatitis (AP) is an acute inflammatory gastrointestinal disease, the mortality and morbility of which has been on the increase in the past years. Spermidine, a natural polyamine, has a wide range of pharmacological effects including anti-inflammation, antioxidation, anti-aging, and anti-tumorigenic. This study aimed to investigate the reliable targets and molecular mechanisms of spermidine in treating AP. By employing computational biology methods including network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we explored the potential targets of spermidine in improving AP with dietary supplementation. The computational biology results revealed that spermidine had high degrees (degree: 18, betweenness: 38.91; degree: 18, betweenness: 206.41) and stable binding free energy (ΔGbind: - 12.81 ± 0.55kcal/mol, - 15.00 ± 1.00kcal/mol) with acetylcholinesterase (AchE) and serotonin transporter (5-HTT). Experimental validation demonstrates that spermidine treatment could reduce the necrosis and AchE activity in pancreatic acinar cells. Cellular thermal shift assay (CETSA) results revealed that spermidine could bind to and stabilize the 5-HTT protein in acinar cells. Moreover, spermidine treatment impeded the rise of the expression of 5-HTT in pancreatic tissues of caerulein induced acute pancreatitis mice. In conclusion, serotonin transporter might be a reliable target of spermidine in treating AP. This study provides new idea for the exploration of potential targets of natural compounds.

Integrated metabolomics, network pharmacology, and molecular docking to reveal the mechanisms of Isodon excisoides against drug-induced liver injury.

Isodon excisoides (Y.Z.Sun ex C.H.Hu) H. Hara has been often used to treat liver diseases in folk medicine. However, the potential hepatoprotective mechanism of I.excisoides remains unclear. In this study, the mechanism of I.excisoides in alleviating drug-induced liver injury (DILI) was explored using a strategy combining metabolomics with network pharmacology for the first time. First, serum metabolomics was applied to identify differential metabolites and enrich metabolic pathways. The potential targets of I.excisoides for the treatment of DILI were investigated by network pharmacology. Subsequently, a comprehensive network of network pharmacology and metabolomics was established to find the key genes. Finally, molecular docking technology was used to further verify the key targets. As a result, four key genes including TYMS, IMPDH2, DHODH, and ASAH1 were identified. The proteins produced by these genes had high affinity with the corresponding diterpenoids. These results indicate that the components of I.excisoides play a liver-protective role by affecting the aforesaid key genes and key proteins. Our results offer a novel strategy for determining the pharmacological effects and potential targets of natural compounds.

Antiviral and anti-inflammatory activity of natural compounds against Japanese encephalitis virus via inhibition of NS5 protein and regulation of key immune and inflammatory signaling pathways.

Japanese encephalitis virus (JEV) is the foremost cause of viral encephalitis in Southeast Asia and Australia leading to approximately 68 000 clinical cases and about 13 600-20 400 deaths annually. Vaccination is not completely sure and safe. Despite this, no specific antiviral has been available or approved for JEV infection yet and treatment is generally symptomatic. Therefore, this study aims to examine the antiviral activity of natural compounds against JEV proteins. The antiviral activity of natural compounds was investigated via molecular docking, cytopathic effect (CPE) inhibition assay, western blotting, and indirect immunofluorescence assay. Physiochemical, pharmacokinetics, and toxicity analysis were evaluated for the safety and efficacy of natural compounds. Network pharmacology-based approaches have been used to study the molecular mechanisms of drug-target interactions. Molecular docking results suggested that the NS5 protein of JEV is the major target for natural compounds. Network pharmacology-based analysis revealed that these drugs majorly target IL6, AKT1, tumor necrosis factor (TNF), and PTGS2 to regulate key immune and inflammatory pathways such as nuclear factor kappa B, PI3K-Akt, and TNF signaling, during JEV infection. Our in vitro results show that among the natural compounds, curcumin provides the highest protection against JEV infection via reducing the JEV-induced CPE (IC50 = 5.90 ± 0.44 µM/mL), and reduces the expression of NS5 protein, IL6, AKT1, TNF-α, and PTGS2. However, other natural compounds also provide protection to some extent but their efficacy is lower compared to curcumin. Therefore, this study shows that natural compounds, mainly curcumin, may offer novel therapeutic avenues for the treatment of JEV via inhibiting key viral proteins and regulating crucial host pathways involved in JEV replication.

The Role of Natural and Semi-Synthetic Compounds in Ovarian Cancer: Updates on Mechanisms of Action, Current Trends and Perspectives.

Ovarian cancer represents a major health concern for the female population: there is no obvious cause, it is frequently misdiagnosed, and it is characterized by a poor prognosis. Additionally, patients are inclined to recurrences because of metastasis and poor treatment tolerance. Combining innovative therapeutic techniques with established approaches can aid in improving treatment outcomes. Because of their multi-target actions, long application history, and widespread availability, natural compounds have particular advantages in this connection. Thus, effective therapeutic alternatives with improved patient tolerance hopefully can be identified within the world of natural and nature-derived products. Moreover, natural compounds are generally perceived to have more limited adverse effects on healthy cells or tissues, suggesting their potential role as valid treatment alternatives. In general, the anticancer mechanisms of such molecules are connected to the reduction of cell proliferation and metastasis, autophagy stimulation and improved response to chemotherapeutics. This review aims at discussing the mechanistic insights and possible targets of natural compounds against ovarian cancer, from the perspective of medicinal chemists. In addition, an overview of the pharmacology of natural products studied to date for their potential application towards ovarian cancer models is presented. The chemical aspects as well as available bioactivity data are discussed and commented on, with particular attention to the underlying molecular mechanism(s).

Transcription Factors as Targets of Natural Compounds in Age-Related Diseases and Cancer: Potential Therapeutic Applications.

Inflammation exacerbates systemic pathophysiological conditions and chronic inflammation is a sustained and systemic phenomenon that aggravates aging that can lead to chronic age-related diseases. These inflammatory phenomena have recently been redefined and delineated at the molecular, cellular, and systemic levels. Many transcription factors that are activated in response to tumor metabolic state have been reported to be regulated by a class of histone deacetylase called sirtuins (SIRTs). Sirtuins play a pivotal role in the regulation of tumor cell metabolism, proliferation, and angiogenesis, including oxidative stress and inflammation. The SIRT1-mediated signaling pathway in diabetes and cancer is the SIRT1/forkhead-box class O (FoxO)/nuclear factor-kappa B (NF-κB) pathway. In this review, we describe the accumulation of SIRT1-, NF-κB-, and FoxO-mediated inflammatory processes and cellular proinflammatory signaling pathways. We also describe the proinflammatory mechanisms underlying metabolic molecular pathways in various diseases such as liver cancer and diabetes. Finally, the regulation of cancer and diabetes through the anti-inflammatory effects of natural compounds is highlighted. Evidence from inflammation studies strongly suggests that cells may be a major source of cytokines secreted during various diseases. A better understanding of the mechanisms that underpin the inflammatory response and palliative role of natural compounds will provide insights into the molecular mechanisms of inflammation and various diseases for potential intervention.

Cryptolepine Targets TOP2A and Inhibits Tumor Cell Proliferation in Breast Cancer Cells - An In vitro and In silico Study.

DNA Topoisomerase II Alpha (TOP2A), a protein-coding gene, is central to the replication process and has been found deregulated in several malignancies, including breast cancer. Several therapeutic regimens have been developed and approved for targeting TOP2A and have prolonged the survival of cancer patients. However, due to the inherent nature of the tumor cell to evolve, the earlier positive response turns into a refractory chemoresistance in breast cancer patients. The study's main objective was to analyze the expression pattern and prognostic significance of TOP2A in breast cancer patients and screen new therapeutic molecules targeting TOP2A. We utilized an integrated bioinformatic approach to analyze the expression pattern, genetic alteration, immune association, and prognostic significance of TOP2A in breast cancer (BC) and screened natural compounds targeting TOP2A, and performed an in silico and an in vitro analysis. Our study showed that TOP2A is highly overexpressed in breast cancer tissues and overexpression of TOP2A correlates with worse overall survival (OS) and relapse-free survival (RFS). Moreover, TOP2A showed a high association with tumor stroma, particularly with myeloid-derived suppressor cells. Also, in silico and in vitro analysis revealed cryptolepine as a promising natural compound targeting TOP2A. Cumulatively, this study signifies that TOP2A promotes breast cancer progression, and targeting TOP2A in combination with other therapeutic agents will significantly enhance the response of BC patients to therapy and reduce the development of chemoresistance.

In-Silico Study: Potential Inhibitor of Cyclin-Dependent Kinase 6 (CDK6) from Natural Plant Compounds for Melanoma Treatment

Highlights:1. Melanoma is the most aggressive and dangerous type of skin cancer. 2. Cyclin-dependent kinase 6 (CDK6) had a role in melanoma progression.3. Chlorogenic acid, guattegaumerine, luteolin, and acronycine were potential natural compounds in plants as CDK6 inhibitors. AbstractIntroduction: Melanoma is the most aggressive and dangerous type of skin cancer. It usually occurs in the skin because melanocytes originate from the neural crest cells that migrate. A previous study stated misregulation of cyclin-dependent kinase 6 (CDK6) had a role in melanoma progression. This study aimed to identify the potential natural compound targeting and modulating the CDK6.Methods: This was an investigative study using in-silico docking analysis to search for compatible ligands and potential inhibitors to CDK6 protein. This study screened 46 natural compounds based on the drug-likeliness based on Lipinski’s rules of five and used PyRx (AutoDock Vina) software for the initial screening. 10 compounds with the highest binding energy underwent docking simulation using Molecular Operating Environment (MOE) software.Results: Chlorogenic acid, guattegaumerine, luteolin, and acronycine were potential natural compounds in plants as CDK6 inhibitors.Conclusion: This study found that chlorogenic acid was the most potential to be an inhibitor of CDK6 compared to other compounds screened.

Neogambogic acid suppresses characteristics and growth of colorectal cancer stem cells by inhibition of DLK1 and Wnt/β-catenin pathway

PurposeTargeting cancer stem cells (CSCs) may be an efficacious strategy against cancer. We were devoted to exploring the role of neogambogic acid in characteristics and growth of colorectal CSCs. MethodsSW480 and HCT116 cells were treated with neogambogic acid at different concentrations and transfected with siDLK1 and pcDNA3.1-DLK1 plasmids. The effect of neogambogic acid on the viability of SW480 and HCT116 cells was assessed by MTT assay. Spheroid formation assay was adopted to enrich colorectal CSCs from SW480 and HCT116 cells. The effect of neogambogic acid on colony number, aldehyde dehydrogenase (ALDH) level, apoptosis and cell cycle of SW480 and HCT116 CSCs was detected by colony formation and flow cytometry assays. The expressions of CSC markers, proliferation marker (proliferation nuclear antigen (PCNA)), apoptosis markers (cleaved caspase-3, cleaved caspase-9), Wnt/β-catenin pathway markers (P-GSK3β, GSK3β, β-catenin and Wnt) and DLK1 were determined by qRT-PCR or Western blot. ResultsNeogambogic acid suppressed viability, the spheroid formation ability and the levels of CSC markers in colorectal cancer (CRC) cells, accompanied with inhibition of colony-formation and ALDH level, apoptosis induction and G0/G1 phase arrest. Furthermore, neogambogic acid inhibited expressions of PCNA, P-GSK3β, P-GSK3β/GSK3β, β-catenin and Wnt, but promoted those of cleaved caspase-3, cleaved caspase-9 and GSK3β in colorectal CSCs. DLK1 silencing caused opposite results. DLK1 overexpression abrogated the effects of neogambogic acid on colorectal CSCs. ConclusionNeogambogic acid could be an efficacious natural compound targeting colorectal CSCs via inhibition of DLK1 and Wnt/β-catenin pathway. Thus, neogambogic acid may be an attractive agent against CRC.

The Signaling Pathways and Targets of Natural Compounds from Traditional Chinese Medicine in Treating Ischemic Stroke.

Ischemic stroke (IS) is a common neurological disorder associated with high disability rates and mortality rates. At present, recombinant tissue plasminogen activator (r-tPA) is the only US(FDA)-approved drug for IS. However, due to the narrow therapeutic window and risk of intracerebral hemorrhage, r-tPA is currently used in less than 5% of stroke patients. Natural compounds have been widely used in the treatment of IS in China and have a wide range of therapeutic effects on IS by regulating multiple targets and signaling pathways. The keywords “ischemia stroke, traditional Chinese Medicine, Chinese herbal medicine, natural compounds” were used to search the relevant literature in PubMed and other databases over the past five years. The results showed that JAK/STAT, NF-κB, MAPK, Notch, Nrf2, and PI3K/Akt are the key pathways, and SIRT1, MMP9, TLR4, HIF-α are the key targets for the natural compounds from traditional Chinese medicine in treating IS. This study aims to update and summarize the signaling pathways and targets of natural compounds in the treatment of IS, and provide a base of information for the future development of effective treatments for IS.

Network Pharmacology-Based Approach Combined with Bioinformatic Analytics to Elucidate the Potential of Curcumol against Hepatocellular Carcinoma.

Purpose: Modern, open-source databases provide an unprecedented wealth of information to help drug development. By combining data available in these databases with the proper bioinformatical tools, we can elucidate the molecular targets of natural compounds. One such molecule is curcumol, a guaiane-type sesquiterpenoid hemiketal isolated from Rhizoma Curcumae, which is used for a broad range of diseases in traditional Chinese and Indian medicine. It has been reported to exert anti-tumor activity, but the intrinsic molecular mechanism in hepatocellular carcinoma (HCC) is unclear. Therefore, the present study was designed to reveal the predictive targets and biological mechanisms of curcumol against HCC via a network pharmacology-based approach combined with bioinformatic analytics and to provide proof of concept for further similar investigations. Methods: Data available from open-source databases (Traditional Chinese Medicine Systems Pharmacology, Comparative Toxicogenomic Database, The Cancer Genome Atlas, the Human Protein Atlas project) was processed with the help of a variety of open-source tools (SwissADME, SwissTargetPrediction, JVenn, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, GeneMANIA, Cytoscape). Results: In the present study, the potential of curcumol against HCC was unraveled by network pharmacology-based elucidation. It suggests that curcumol shows exciting druggability with 44 potent homo sapiens biotargets against HCC. The GO terms and KEGG pathways enrichment analyses, curcumol-targets-pathways-HCC network, PPI network, and corresponding in-depth topological analyses, as well as survival analysis, molecular docking simulation indicate that the potential mechanism of curcumol against HCC is complicated, as it may act in various ways, mainly by inducing apoptosis and modulating the inflammatory response, increasing presentation of HCC-specific protein. Conclusion: The present study highlights the potential of curcumol against HCC, giving reference to further experimental study. It also presents a roadmap that can be followed to conduct in silico prescreening of other compounds of interest.

Recent Progress in Understanding the Action of Natural Compounds at Novel Therapeutic Drug Targets for the Treatment of Liver Cancer.

Liver cancer is the third most common cause of cancer-related death following lung and stomach cancers. As a highly lethal disease, liver cancer is diagnosed frequently in less developed countries. Natural compounds extracted from herbs, animals and natural materials have been adopted by traditional Chinese medicine (TCM) practices and reported to be effective in the development of new medications for the treatment of diseases. It is important to focus on the mechanisms of action of natural compounds against hepatocellular carcinoma (HCC), particularly in terms of cell cycle regulation, apoptosis induction, autophagy mediation and cell migration and invasion. In this review, we characterize novel representative natural compounds according to their pharmacologic effects based on recently published studies. The aim of this review is to summarize and explore novel therapeutic drug targets of natural compounds, which could accelerate the discovery of new anticancer drugs.

Molecular Targets of Natural Compounds with Anti-Cancer Properties.

Cancer is the second leading cause of death in humans. Despite rapid developments in diagnostic methods and therapies, metastasis and resistance to administrated drugs are the main obstacles to successful treatment. Therefore, the main challenge should be the diagnosis and design of optimal therapeutic strategies for patients to increase their chances of responding positively to treatment and increase their life expectancy. In many types of cancer, a deregulation of multiple pathways has been found. This includes disturbances in cellular metabolism, cell cycle, apoptosis, angiogenesis, or epigenetic modifications. Additionally, signals received from the microenvironment may significantly contribute to cancer development. Chemical agents obtained from natural sources seem to be very attractive alternatives to synthetic compounds. They can exhibit similar anti-cancer potential, usually with reduced side effects. It was reported that natural compounds obtained from fruits and vegetables, e.g., polyphenols, flavonoids, stilbenes, carotenoids and acetogenins, might be effective against cancer cells in vitro and in vivo. Several published results indicate the activity of natural compounds on protein expression by its influence on transcription factors. They could also be involved in alterations in cellular response, cell signaling and epigenetic modifications. Such natural components could be used in our diet for anti-cancer protection. In this review, the activities of natural compounds, including anti-cancer properties, are described. The influence of natural agents on cancer cell metabolism, proliferation, signal transduction and epigenetic modifications is highlighted.

Bioactive Compounds as Potential Agents for Sexually Transmitted Diseases Management: A Review to Explore Molecular Mechanisms of Action.

Sexually transmitted diseases (STDs) are produced by pathogens like bacteria, fungi, parasites, and viruses, and may generate severe health problems such as cancer, ulcers, and even problems in the newborn. This narrative review aims to present updated information about the use of natural bioactive compounds for the prevention and treatment of sexually transmitted infections. A search of the literature was performed using databases and search engines such as PubMed, Scopus, Google Scholar and Science Direct. From the pharmacotherapeutic management point of view, any strategies for prevention should contain medical approaches. The bioactive compounds obtained from natural products have shown biological effects against different microorganisms for the treatment of these diseases. The main results showed antimicrobial, antiprotozoal, antifungal and antiviral effects such as HIV. Also, the molecular mechanisms, signalling pathways and action targets of natural compounds were highlighted, thus justifying bacterial and antifungal inhibition, apoptosis or reduction of viral replication. From the data of our study, we can conclude that natural compounds may be a significant source for adjuvant drugs / complementary therapies in the treatment of STDs. With all these benefits, the future must conduct extensive clinical trials and the development of pharmaceutical nanotechnologies for a greater therapeutic effect.

Identification and evaluation of antiviral potential of thymoquinone, a natural compound targeting Chikungunya virus capsid protein

Capsid protein (CP) of Chikungunya virus (CHIKV) is a multifunctional protein with a conserved hydrophobic pocket that plays a crucial role in the capsid assembly and virus budding process. This study demonstrates antiviral activity of thymoquinone (TQ), a natural compound targeting the hydrophobic pocket of CP. The binding of TQ to the hydrophobic pocket of CHIKV CP was analysed by structure-based molecular docking, isothermal titration calorimetry and fluorescence spectroscopy. The binding constant KD obtained for TQ was 27 μM. Additionally, cell-based antiviral studies showed that TQ diminished CHIKV replication with an EC50 value 4.478 μM. Reduction in viral RNA copy number and viral replication as assessed by the qRT-PCR and immunofluorescence assay, confirmed the antiviral potential of TQ. Our study reveals that TQ is an effective antiviral targeting the hydrophobic pocket of CHIKV CP and may serve as the basis for development of a broad-spectrum therapy against alphaviral diseases.

Biochemical characterization and inhibition of thermolabile hemolysin fromVibrio parahaemolyticusby phenolic compounds

Vibrio parahaemolyticus (Vp), a typical microorganism inhabiting marine ecosystems, uses pathogenic virulence molecules such as hemolysins to cause bacterial infections of both human and marine animals. The thermolabile hemolysin VpTLH lyses human erythrocytes by a phospholipase B/A2 enzymatic activity in egg-yolk lecithin. However, few studies have been characterized the biochemical properties and the use of VpTLH as a molecular target for natural compounds as an alternative to control Vp infection. Here, we evaluated the biochemical and inhibition parameters of the recombinant VpTLH using enzymatic and hemolytic assays and determined the molecular interactions by in silico docking analysis. The highest enzymatic activity was at pH 8 and 50 °C, and it was inactivated by 20 min at 60 °C with Tm = 50.9 °C. Additionally, the flavonoids quercetin, epigallocatechin gallate, and morin inhibited the VpTLH activity with IC50 values of 4.5 µM, 6.3 µM, and 9.9 µM, respectively; while phenolics acids were not effective inhibitors for this enzyme. Boltzmann and Arrhenius equation analysis indicate that VpTLH is a thermolabile enzyme. The inhibition of both enzymatic and hemolytic activities by flavonoids agrees with molecular docking, suggesting that flavonoids could interact with the active site’s amino acids. Future research is necessary to evaluate the antibacterial activity of flavonoids against Vp in vivo.

Molecular Basis of the Antiangiogenic Action of Rosmarinic Acid, a Natural Compound Targeting Fibroblast Growth Factor‐2/FGFR Interactions

Fibroblast growth factor (FGF2)/fibroblast growth factor receptor (FGFR) signalling plays a major role both in physiology and in several pathologies, including cancer development, metastasis formation and resistance to therapy. The development of small molecules, acting extracellularly to target FGF2/FGFR interactions, has the advantage of limiting the adverse effects associated with current intracellular FGFR inhibitors. Herein, we discuss the ability of the natural compound rosmarinic acid (RA) to induce FGF2/FGFR complex dissociation. The molecular-level description of the FGF2/FGFR/RA system, by NMR spectroscopy and docking, clearly demonstrates that RA binds to the FGFR-D2 domain and directly competes with FGF2 for the same binding site. Direct and allosteric perturbations combine to destabilise the complex. The proposed molecular mechanism is validated by cellular studies showing that RA inhibits FGF2-induced endothelial cell proliferation and FGFR activation. Our results can serve as the basis for the development of new extracellular inhibitors of the FGF/FGFR pathways.