Phytotherapeutic options for the treatment of epilepsy: pharmacology, targets, and mechanism of action.

Epilepsy is one of the most common, severe, chronic, potentially life-shortening neurological disorders, characterized by a persisting predisposition to generate seizures. It affects more than 60 million individuals globally, which is one of the major burdens in seizure-related mortality, comorbidities, disabilities, and cost. Different treatment options have been used for the management of epilepsy. More than 30 drugs have been approved by the US FDA against epilepsy. However, one-quarter of epileptic individuals still show resistance to the current medications. About 90% of individuals in low and middle-income countries do not have access to the current medication. In these countries, plant extracts have been used to treat various diseases, including epilepsy. These medicinal plants have high therapeutic value and contain valuable phytochemicals with diverse biomedical applications. Epilepsy is a multifactorial disease, and therefore, multitarget approaches such as plant extracts or extracted phytochemicals are needed, which can target multiple pathways. Numerous plant extracts and phytochemicals have been shown to treat epilepsy in various animal models by targeting various receptors, enzymes, and metabolic pathways. These extracts and phytochemicals could be used for the treatment of epilepsy in humans in the future; however, further research is needed to study the exact mechanism of action, toxicity, and dosage to reduce their side effects. In this narrative review, we comprehensively summarized the extracts of various plant species and purified phytochemicals isolated from plants, their targets and mechanism of action, and dosage used in various animal models against epilepsy.

A comprehensive investigation on alleviating oxidative stress and inflammation in hyperglycaemic conditions through in vitro experiments and computational analysis.

Protein glycation, hyper-inflammatory reactions, and oxidative stress play a crucial role in the pathophysiology of numerous diseases. The current work evaluated the protective ability of ethyl alcohol extract of leaves from holy basil (Ocimum sanctum Linn) against inflammation, oxidative stress, glycation and advanced glycation endproducts formation. Various in vitro assays assessed prementioned properties of holy basil. In addition, molecular docking was conducted. The highest hydrogen peroxide reduction activity (72.7 %) and maximum percentage of DPPH scavenging (71.3 %) depicted its vigorous antioxidant abilities. Furthermore, it showed the most excellent protection against proteinase activity (67.247 %), prevention of denaturation of egg albumin (65.29 %), and BSA (bovine serum albumin) (68.87 %) with 600 µg/ml. Percent aggregation index (57.528 %), browning intensity (56.61 %), and amyloid structure (57.0 %) were all reduced significantly using 600 µg/ml of extract. Additionally, the antimicrobial potential was also confirmed. According to a molecular docking study, active leaf extract ingredients were found to bind with superoxide dismutase, catalase, and carbonic anhydrase. As a conclusion, O. sanctum has a variety of health-promoting properties that may reduce the severity of many diseases in diabetic patients. However, in order to ascertain the mechanisms of action of the components of its leaves in disease prevention, more thorough research based on pharmacological aspects is needed.

Unveiling the Molecular Interactions Between Human Transferrin and Limonene: Natural Compounds in Alzheimer's Disease Therapeutics.

Background: Neurodegeneration is a term describing an irreversible process of neuronal damage. In recent decades, research efforts have been directed towards deepening our knowledge of numerous neurodegenerative disorders, with a particular focus on conditions such as Alzheimer's disease (AD). Human transferrin (htf) is a key player in maintaining iron homeostasis within brain cells. Any disturbance in this equilibrium gives rise to the emergence of neurodegenerative diseases and associated pathologies, particularly AD. Limonene, a natural compound found in citrus fruits and various plants, has shown potential neuroprotective properties. Objective: In this study, our goal was to unravel the binding of limonene with htf, with the intention of comprehending the interaction mechanism of limonene with htf. Methods: Binding was scrutinized using fluorescence quenching and UV-Vis spectroscopic analyses. The binding mechanism of limonene was further investigated at the atomic level through molecular docking and extensive 200 ns molecular dynamic simulation (MD) studies. Results: Molecular docking uncovered that limonene interacted extensively with the deep cavity located within the htf binding pocket. MD results indicated that binding of limonene to htf did not induce substantial structural alterations, ultimately forming stable complex. The findings from fluorescence binding indicated a pronounced interaction between limonene and htf, limonene binds to htf with a binding constant (K) of 0.1×105 M-1. UV spectroscopy also advocated stable htf-limonene complex formation. Conclusions: The study deciphered the binding mechanism of limonene with htf, providing a platform to use limonene in AD therapeutics in context of iron homeostasis.

Comprehensive spectroscopic and computational insight into the binding of vanillin with human transferrin: targeting neuroinflammation in Alzheimer's disease therapeutics.

In present times, vanillin stands out as a promising therapeutic molecule that can be implicated in the treatment of neurodegenerative disorders (NDs), notably Alzheimer's disease (AD). This can be attributed to the highly potent scavenging activity of vanillin against reactive oxygen species (ROS). Oxidative stress leads to generation of ROS that serves a critical role in AD's pathological progression. It is apparent from various studies that diets rich in polyphenols prevent oxidative stress associated with AD development, implying the crucial role of vanillin in AD therapeutics. It is crucial to maintain iron balance to manage AD associated oxidative stress, unveiling the significance of human transferrin (hTf) that maintains iron homeostasis. Here, we have performed an integrated study of spectroscopic and computational approaches to get insight into the binding mechanism of vanillin with hTf. In the preliminary study, molecular docking deciphered that vanillin primarily occupies the hTf binding pocket, forming multiple interactions with its key residues. Moreover, the binding mechanism was evaluated at an atomistic level employing comprehensive molecular dynamic (MD) simulation. MD analysis demonstrated that binding of vanillin to hTf stabilizes its structure, without inducing any significant alterations in its native conformation. The docked complex was maintained throughout the simulations without changing its original conformation. Essential dynamics analysis further confirms that hTf achieved a stable conformation with vanillin. The outcomes were further supplemented by fluorescence spectroscopy which confirms the formation of stable hTf-vanillin complex. Taken together, the current study unveils the interaction mechanism of vanillin with hTf and providing a platform to use vanillin in AD therapeutics in the context of iron homeostasis.

Various pharmacological agents in the pipeline against intractable epilepsy.

Epilepsy is a noncommunicable chronic neurological disorder affecting people of all ages, with the highest prevalence in low and middle-income countries. Despite the pharmacological armamentarium, the plethora of drugs in the market, and other treatment options, 30%-35% of individuals still show resistance to the current medication, termed intractable epilepsy/drug resistance epilepsy, which contributes to 50% of the mortalities due to epilepsy. Therefore, the development of new drugs and agents is needed to manage this devastating epilepsy. We reviewed the pipeline of drugs in "ClinicalTrials. gov," which is the federal registry of clinical trials to identify drugs and other treatment options in various phases against intractable epilepsy. A total of 31 clinical trials were found regarding intractable epilepsy. Among them, 48.4% (15) are about pharmacological agents, of which 26.6% are in Phase 1, 60% are in Phase 2, and 13.3% are in Phase 3. The mechanism of action or targets of the majority of these agents are different and are more diversified than those of the approved drugs. In this article, we summarized various pharmacological agents in clinical trials, their backgrounds, targets, and mechanisms of action for the treatment of intractable epilepsy. Treatment options other than pharmacological ones, such as devices for brain stimulation, ketogenic diets, gene therapy, and others, are also summarized.

Evaluation of the Binding Mechanism of Dietary Phytochemical, Ellagic Acid, with Human Transferrin: Spectroscopic, Calorimetric, and Computational Approaches Targeting Neurodegenerative Diseases.

Human transferrin (Htf) is vital in maintaining iron within the brain cells; any disruption results in the development of neurodegenerative diseases (NDs) and other related pathologies, especially Alzheimer's disease (AD). Ellagic acid (EA), a naturally occurring phenolic antioxidant, possesses neuroprotective potential and is present in a broad variety of fruits and vegetables. The current work explores the binding mechanism of dietary polyphenol, EA, with Htf by a combination of experimental and computational approaches. Molecular docking studies unveiled the binding of EA to Htf with good affinity. Molecular dynamic (MD) simulation further provided atomistic details of the binding process, demonstrating a stable Htf-EA complex formation without causing substantial alterations to the protein's conformation. Furthermore, fluorescence binding measurements indicated that EA forms a high-affinity interaction with Htf. Isothermal titration calorimetric measurements advocated the spontaneous nature of binding and also revealed the binding process to be exothermic. In conclusion, the study deciphered the binding mechanism of EA with Htf. The results demonstrated that EA binds with Htf with an excellent affinity spontaneously, thereby laying the groundwork for potential applications of EA in the realm of therapeutics for NDs in the context of iron homeostasis.

Evaluation of binding mechanism of dietary phytochemical, capsaicin, with human transferrin: targeting neurodegenerative diseases therapeutics.

Human transferrin (htf) plays a crucial role in regulating the balance of iron within brain cells; any disruption directly contributes to the development of Neurodegenerative Diseases (NDs) and other related pathologies, especially Alzheimer's Disease (AD). In recent times, a transition towards natural compounds is evident to treat diseases and this shift is mainly attributed to their broad therapeutic potential along with minimal side effects. Capsaicin, a natural compound abundantly found in red and chili peppers, possess neuroprotective potential. The current work targets to decipher the interaction mechanism of capsaicin with htf using experimental and computational approaches. Molecular docking analysis revealed that capsaicin occupies the iron binding pocket of htf, with good binding affinity. Further, the binding mechanism was investigated atomistically using Molecular dynamic (MD) simulation approach. The results revealed no significant alterations in the structure of htf implying the stability of the complex. In silico observations were validated by fluorescence binding assay. Capsaicin binds to htf with a binding constant (K) of 3.99 × 106 M-1, implying the stability of the htf-capsaicin complex. This study lays a platform for potential applications of capsaicin in treatment of NDs in terms of iron homeostasis.

Novel mutation in alpha-spectrin gene in Saudi patients with hereditary spherocytosis.

Hereditary spherocytosis (HS) is the most common hereditary hemolytic disorder induced by red blood cell (RBC) membrane defect. This study was undertaken to determine mutations in genes associated with RBC membrane defect in patients with HS such as α-spectrin gene (SPTA1), ß-spectrin gene (SPTB), ankyrin gene (ANK1), band 3 anion transport gene (SLC4A1) and erythrocyte membrane protein band 4.1 gene (EPB41). Blood samples were collected from 23 unrelated patients with HS. Patients were diagnosed according to the guidelines from the British Society for Hematology. All hematological examinations for the determination of RBC abnormalities and osmotic fragility tests were conducted. Genomic DNA were extracted from peripheral blood cells and coding exons of known genes for hereditary spherocytosis were enriched using Roche/KAPA sequence capture technology and sequenced on an Illumina system via next-generation sequencing (NGS). The data showed that most of the HS patients confirmed splenomegaly and showed elevated reticulocytes and abnormal bilirubin values. NGS analysis identified the heterozygous variant c.5501G > A in the exon 39 of SPTA1 gene, resulted in a Trp1834*, which leads to a premature stop codon and subsequent mRNA degradation (nonsense- mediated decay) or truncation in α spectrin. Moreover, our data also revealed conventional mutations in genes SPTB, ANK, SLC4A1 and EBP41 in severe patients of HS. In short, this is the first report that determined a novel mutation c.5501G > A in SPTA1 gene in the Saudi population. To the best of our knowledge, this variant c.5501G > A has not been described in global literature so far. This novel mutation in SPTA1 gene is unique in the Saudi population.

Unlocking therapeutic potential: computational insights into TREM2 protein targeting with FDA-approved drugs for neurodegeneration.

Neurodegenerative diseases such as Alzheimer's disease (AD) pose a significant global health challenge that requires the exploration of innovative therapeutic strategies. Triggering receptor expressed on myeloid cells-2 (TREM2) is one of the critical proteins involved in immune regulation and neuroinflammation. It has emerged as a promising therapeutic target to develop treatments for neurodegenerative disorders like AD. Here, we employed a comprehensive virtual screening approach to identify potential small molecule inhibitors among FDA-approved drugs for TREM2. The docking study reveals significant binding affinity, ranging from -7.8 kcal/mol to -8.5 kcal/mol, for the elucidated hits against TREM2, accompanied by several crucial interactions. Among the repurposed drugs identified in the initial screening, Carpipramine, Clocapramine, and Pimozide stood out due to their notable binding potential and favorable drug profiling. Further, we conducted molecular dynamics (MD) simulations on the selected molecules that probed their structural dynamics and stability within the TREM2 binding pocket. The structural parameters and hydrogen bond dynamics remained remarkably stable throughout the simulated trajectories. Furthermore, we performed principal component analysis (PCA) and constructed free energy landscapes (FELs) to gain deeper insights into ligand binding and conformational flexibility of TREM2. The findings revealed that the elucidated molecules, Carpipramine, Clocapramine, and Pimozide, exhibited an exceptional fit within the binding pocket of TREM2 with remarkable stability and interaction patterns throughout the 500 ns simulation window. Interestingly, these molecules possessed a spectrum of anti-neurodegenerative properties and favorable drug profiles, which suggest their potential as promising drug candidates for repurposing in the treatment of AD.Communicated by Ramaswamy H. Sarma.

Targeting Sirtuin 1 for therapeutic potential: Drug repurposing approach integrating docking and molecular dynamics simulations.

Identifying novel therapeutic agents is a fundamental challenge in contemporary drug development, especially in the context of complex diseases like cancer, neurodegenerative disorders, and metabolic syndromes. Here, we present a comprehensive computational study to identify potential inhibitors of SIRT1 (Sirtuin 1), a critical protein involved in various cellular processes and disease pathways. Leveraging the concept of drug repurposing, we employed a multifaceted approach that integrates molecular docking and molecular dynamics (MD) simulations to predict the binding affinities and dynamic behavior of a diverse set of FDA-approved drugs from DrugBank against the SIRT1. Initially, compounds were shortlisted based on their binding affinities and interaction analyses to identify safe and promising binding partners for SIRT1. Among these candidates, Doxercalciferol and Timiperone emerged as potential candidates, displaying notable affinity, efficiency, and specificity towards the binding pocket of SIRT1. Extensive evaluation revealed that these identified compounds boast a range of favorable biological properties and prefer binding to the active site of SIRT1. To delve deeper into the interactions, all-atom MD simulations were conducted for 500 nanoseconds (ns). These simulations assessed the conformational dynamics, stability, and interaction mechanism of the SIRT1-Doxercalciferol and SIRT1-Timiperone complexes. The MD simulations illustrated that the SIRT1-Doxercalciferol and SIRT1-Timiperone complexes maintain stability over a 500 ns trajectory. These insightful outcomes propose that Doxercalciferol and Timiperone hold promise as viable scaffolds for developing potential SIRT1 inhibitors, with implications for tackling complex diseases such as cancer, neurodegenerative disorders, and metabolic syndromes.

Unlocking potential inhibitors for Bruton's tyrosine kinase through in-silico drug repurposing strategies.

Bruton's tyrosine kinase (BTK) is a non-receptor protein kinase that plays a crucial role in various biological processes, including immune system function and cancer development. Therefore, inhibition of BTK has been proposed as a therapeutic strategy for various complex diseases. In this study, we aimed to identify potential inhibitors of BTK by using a drug repurposing approach. To identify potential inhibitors, we performed a molecular docking-based virtual screening using a library of repurposed drugs from DrugBank. We then used various filtrations followed by molecular dynamics (MD) simulations, principal component analysis (PCA), and Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) analysis to further evaluate the binding interactions and stability of the top-ranking compounds. Molecular docking-based virtual screening approach identified several repurposed drugs as potential BTK inhibitors, including Eltrombopag and Alectinib, which have already been approved for human use. All-atom MD simulations provided insights into the binding interactions and stability of the identified compounds, which will be helpful for further experimental validation and optimization. Overall, our study demonstrates that drug repurposing is a promising approach to identify potential inhibitors of BTK and highlights the importance of computational methods in drug discovery.

Unveiling Phytoconstituents with Inhibitory Potential Against Tyrosine-Protein Kinase Fyn: A Comprehensive Virtual Screening Approach Targeting Alzheimer's Disease.

BACKGROUND: Tyrosine-protein kinase Fyn (Fyn) is a critical signaling molecule involved in various cellular processes, including neuronal development, synaptic plasticity, and disease pathogenesis. Dysregulation of Fyn kinase has been implicated in various complex diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, as well as different cancer types. Therefore, identifying small molecule inhibitors that can inhibit Fyn activity holds substantial significance in drug discovery. OBJECTIVE: The aim of this study was to identify potential small-molecule inhibitors among bioactive phytoconstituents against tyrosine-protein kinase Fyn. METHODS: Through a comprehensive approach involving molecular docking, drug likeliness filters, and molecular dynamics (MD) simulations, we performed a virtual screening of a natural compounds library. This methodology aimed to pinpoint compounds potentially interacting with Fyn kinase and inhibiting its activity. RESULTS: This study finds two potential natural compounds: Dehydromillettone and Tanshinone B. These compoundsdemonstrated substantial affinity and specific interactions towards the Fyn binding pocket. Their conformations exhibitedcompatibility and stability, indicating the formation of robust protein-ligand complexes. A significant array of non-covalentinteractions supported the structural integrity of these complexes. CONCLUSION: Dehydromillettone and Tanshinone B emerge as promising candidates, poised for further optimization as Fynkinase inhibitors with therapeutic applications. In a broader context, this study demonstrates the potential of computationaldrug discovery, underscoring its utility in identifying compounds with clinical significance. The identified inhibitors holdpromise in addressing a spectrum of cancer and neurodegenerative disorders. However, their efficacy and safety necessitatevalidation through subsequent experimental studies.

Role of Th17 and IL-17 Cytokines on Inflammatory and Auto-immune Diseases.

BACKGROUND: The IL-17 (interleukin 17) family consists of six structurally related pro-inflammatory cytokines, namely IL-17A to IL-17F. These cytokines have garnered significant scientific interest due to their pivotal role in the pathogenesis of various diseases. Notably, a specific subset of T-cells expresses IL-17 family members, highlighting their importance in immune responses against microbial infections. INTRODUCTION: IL-17 cytokines play a critical role in host defense mechanisms by inducing cytokines and chemokines, recruiting neutrophils, modifying T-cell differentiation, and stimulating the production of antimicrobial proteins. Maintaining an appropriate balance of IL-17 is vital for overall health. However, dysregulated production of IL-17A and other members can lead to the pathogenesis of numerous inflammatory and autoimmune diseases. METHOD: This review provides a comprehensive overview of the IL-17 family and its involvement in several inflammatory and autoimmune diseases. Relevant literature and research studies were analyzed to compile the data presented in this review. RESULTS: IL-17 cytokines, particularly IL-17A, have been implicated in the development of various inflammatory and autoimmune disorders, including multiple sclerosis, Hashimoto's thyroiditis, systemic lupus erythematosus, pyoderma gangrenosum, autoimmune hepatic disorders, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, and graft-versus-host disease. Understanding the role of IL-17 in these diseases is crucial for developing targeted therapeutic strategies. CONCLUSION: The significant involvement of IL-17 cytokines in inflammatory and autoimmune diseases underscores their potential as therapeutic targets. Current treatments utilizing antibodies against IL-17 cytokines and IL-17RA receptors have shown promise in managing these conditions. This review consolidates the understanding of IL-17 family members and their roles, providing valuable insights for the development of novel immunomodulators to effectively treat inflammatory and autoimmune diseases.

Unveiling promising inhibitors of superoxide dismutase 1 (SOD1) for therapeutic interventions.

Superoxide dismutase 1 (SOD1) is a vital enzyme responsible for controlling cellular oxidative stress. Any dysregulation of SOD1 activity is linked with cancer pathogenesis and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Among the inhibitors known to be effective against SOD1, LCS-1 stands out; however, its efficacy, specificity, and safety profiles are somewhat restricted. In this study, we used PubChem library to retrieve compounds that exhibited a structural similarity of at least 90 % with LCS-1. These compounds underwent molecular docking analyses to examine their interaction patterns and binding affinities with SOD1. Further, we applied filters based on physicochemical and ADMET properties, refining the selection process. Our analysis revealed that selected compounds interact with crucial residues of SOD1 active site. To gain further insights into conformational stability and dynamics of the SOD1-ligand complexes, we conducted all-atom molecular dynamics (MD) simulations for 100 ns. We identified two compounds, CID:133306073 and CID:133446715, as potential scaffolds with promising inhibitory properties against SOD1. Both compounds hold significant potential for further exploration as therapeutic SOD1 inhibitors. Further studies are warranted to fully harness their therapeutic potential in targeting SOD1 for cancer and ALS treatment, offering new avenues for improved patient outcomes and disease management.

Identifying ß-secretase 1 (BACE1) inhibitors from plant-based compounds: an approach targeting Alzheimer's therapeutics employing molecular docking and dynamics simulation.

ß-secretase 1 (BACE1) is an enzyme that is involved in generating beta-amyloid peptides and is believed to have a significant role in the development of Alzheimer's disease (AD). Therefore, BACE1 has gained attention as a potential therapeutic target for treating AD. Modern drug discovery studies are being conducted to identify potential inhibitors of BACE1, with the goal of reducing the production of beta-amyloid peptides and, thus, slowing the progression of AD. Here, we used a multistep virtual screening methodology to identify phytoconstituents from the IMPPAT library that could inhibit the activity of BACE1. Molecular docking was employed to select initial hits based on their binding affinity toward BACE1. Screening for PAINS patterns, ADMET and PASS properties, was then used to identify potential molecules for BACE1 inhibition. In the end, we discovered two natural compounds, Peiminine and 27-Deoxywithaferin A, which demonstrated a strong affinity, effectiveness, and specific interactions for the BACE1-active site. The elucidated molecules also displayed drug likeliness. A 200 ns molecular dynamics (MD) simulation was conducted to investigate the interaction mechanism, complex stability, and conformational dynamics of BACE1 with Peiminine and 27-Deoxywithaferin A. The MD simulations demonstrated that BACE1 was stable during the simulation with Peiminine and 27-Deoxywithaferin A. Overall, the results suggested that Peiminine and 27-Deoxywithaferin A hold significant potential as scaffolds in drug development efforts targeting BACE1 for the purpose of treating AD.

Therapeutic Potential and Molecular Mechanisms of the Multitargeted Flavonoid Fisetin.

Flavonoids effectively treat cancer, inflammatory disorders (cardiovascular and nervous systems), and oxidative stress. Fisetin, derived from fruits and vegetables, suppresses cancer growth by altering cell cycle parameters that lead to cell death and angiogenesis without affecting healthy cells. Clinical trials are needed in humans to prove the effectiveness of this treatment for a wide range of cancers. According to the results of this study, fisetin can be used to prevent and treat a variety of cancers. Despite early detection and treatment advances, cancer is the leading cause of death worldwide. We must take proactive steps to reduce the risk of cancer. The natural flavonoid fisetin has pharmacological properties that suppress cancer growth. This review focuses on the potential drug use of fisetin, which has been extensively explored for its cancer-fighting ability and other pharmacological activities such as diabetes, COVID-19, obesity, allergy, neurological, and bone disorders. Researchers have focused on the molecular function of fisetin. In this review, we have highlighted the biological activities against chronic disorders, including cancer, metabolic illnesses, and degenerative illnesses, of the dietary components of fisetin.

PF543-like compound, a promising sphingosine kinase 1 inhibitor: Structure-based virtual screening and molecular dynamic simulation approaches.

Sphingosine kinase 1 (SphK1) has been widely recognized as a significant contributor to various types of cancer, including breast, lung, prostate, and hematological cancers. This research aimed to find a potential SphK1 inhibitor through a step-by-step virtual screening of PF543 (a known SphK1 inhibitor)-like compounds obtained from the PubChem library with the Tanimoto threshold of 80 %. The virtual screening process included several steps, namely physicochemical and ADMET evaluation, PAINS filtering, and molecular docking, followed by molecular dynamics (MD) simulation and principal component analysis (PCA). The results showed that compound CID:58293960 ((3R)-1,1-dioxo-2-[[3-[(4-phenylphenoxy)methyl]phenyl]methyl]-1,2-thiazolidine-3-carboxylic acid) demonstrated high potential as SphK1 inhibitor. All-atom MD simulations were performed for 100 ns to evaluate the stability and structural changes of the docked complexes in an aqueous environment. The analysis of the time evolution data of structural deviations, compactness, PCA, and free energy landscape (FEL) indicated that the binding of CID:58293960 with SphK1 is relatively stable throughout the simulation. The results of this study provide a platform for the discovery and development of new anticancer therapeutics targeting SphK1.