Docking Approach Research Articles

Modeling Ligand Binding Site Water Networks with Site Identification by Ligand Competitive Saturation: Impact on Ligand Binding Orientations and Relative Binding Affinities.

Appropriate treatment of water contributions to protein-ligand interactions is a very challenging problem in the context of adequately determining the number of waters to investigate and undertaking conformational sampling of the ligands, the waters, and the surrounding protein. In the present study, an extension of the Site Identification by Ligand Competitive Saturation-Monte Carlo (SILCS-MC) docking approach is presented that enables the determination of the location of water molecules in the binding pocket and their impact on the predicted ligand binding orientation and affinities. The approach, termed SILCS-WATER, involves MC sampling of the ligand along with explicit water molecules in a binding site followed by selection of a subset of waters within specified energetic and distance cutoffs that contribute to ligand binding and orientation. To allow for convergence of both the water and ligand orientations, SILCS-WATER is based on just the overlap of the ligand and water with the SILCS FragMaps and the interaction energy between the waters and ligand. Results show that the SILCS-WATER methodology can capture important waters and improve ligand binding orientations. For 6 of 10 multiple ligand-protein systems, the method improved relative binding affinity prediction against experimental results, with substantial improvements in five systems, when compared to standard SILCS-MC. Improved reproduction of crystallographic ligand binding orientations is shown to be an indicator of when SILCS-WATER will yield improved binding affinity correlations. The method also identifies waters interacting with ligands that occupy unfavorable locations with respect to the protein whose displacement through the appropriate ligand modifications should improve ligand binding affinity. Results are consistent with the binding affinity being modeled as a ligand-water complex interacting with the protein. The presented approach offers new possibilities in revealing water networks and their contributions to the binding orientation and affinity of a ligand for a protein and is anticipated to be of utility for computer-aided drug design.

Multiomics and Molecular Docking Approaches to Elucidate Desmostachya Bipinnata-Derived Multitargeting Agents for Oral Squamous Cell Carcinoma

Multiomics and Molecular Docking Approaches to Elucidate Desmostachya Bipinnata-Derived Multitargeting Agents for Oral Squamous Cell Carcinoma

Ultra-Large Virtual Screening: Definition, Recent Advances, and Challenges in Drug Design.

Virtual screening (VS) in drug design employs computational methodologies to systematically rank molecules from a virtual compound library based on predicted features related to their biological activities or chemical properties. The recent expansion in commercially accessible compound libraries and the advancements in artificial intelligence (AI) and computational power - including enhanced central processing units (CPUs), graphics processing units (GPUs), high-performance computing (HPC), and cloud computing - have significantly expanded our capacity to screen libraries containing over 109 molecules. Herein, we review the concept of ultra-large virtual screening (ULVS), focusing on the various algorithms and methodologies employed for virtual screening at this scale. In this context, we present the software utilized, applications, and results of different approaches, such as brute force docking, reaction-based docking approaches, machine learning (ML) strategies applied to docking or other VS methods, and similarity/pharmacophore search-based techniques. These examples represent a paradigm shift in the drug discovery process, demonstrating not only the feasibility of billion-scale compound screening but also their potential to identify hit candidates and increase the structural diversity of novel compounds with biological activities.

Ruthenium Complexes with Pyridazine Carboxylic Acid: Synthesis, Characterization, and Anti-Biofilm Activity

As a result of drug resistance, many antimicrobial medicines become ineffective, making the infections more difficult to treat. Therefore, there is a need to develop new compounds with antibacterial activity. This role may be played, for example, by metal complexes with carboxylic acids. This study reports the formation and characterization of ruthenium complexes with pyridazine-3-carboxylic acid (pdz-3-COOH)—([(η6-p-cym)RuIICl(pdz-3-COO)] (1), [RuIIICl2(pdz-3-COO)2Na(H2O)]n(H2O)0.11 (2) and [RuIIICl2(pdz-3-COO)2Na(H2O)2]n (3). The synthesized compounds were analyzed using various spectroscopic and electrochemical techniques, with structure confirmation via SC-XRD analysis. Experimental data showed the ligand binds to metal ions bidentately through the nitrogen donor of the pyridazine ring and one carboxylate oxygen. To visualize intermolecular interactions, Hirshfeld surface analysis and 2D fingerprint plots were conducted. Furthermore, the impact of ruthenium compounds (1 and 2) on the planktonic growth of selected bacterial strains and the formation of Pseudomonas aeruginosa PAO1 biofilm was examined. Both complexes demonstrated comparable anti-biofilm activity and outperformed the free ligand. The effect of the complexes on selected virulence factors of P. aeruginosa PAO1 was also investigated. Compounds 1 and 2 show high suppressive activity in pyoverdine production, indicating that the virulence of the strain has been reduced. This inhibitory effect is similar to the inhibitory effect of ciprofloxacin. Within this context, the complexes exhibit promising antibacterial activities. Importantly, the compounds showed no cytotoxic effects on normal CHO-K1 cells. Additionally, a molecular docking approach and fluorescence spectroscopy were used to determine the interactions of ruthenium complexes with human serum albumin.

Probing the potential mechanism of permethrin exposure on Alzheimer's disease through enantiomer-specific network toxicology, multi-spectroscopic, and docking approaches

Latest observations indicated that exposure of organic environmental neurotoxins may increase the potential risk of Alzheimer's diseases (AD). As a suspected food-derived risk factor, permethrin, composed of cis-isomer and trans-isomer, is widely used as a broad-spectrum pyrethroid insecticide in agricultural crops for the arthropod pests controlling. Thus, evaluating the impact of permethrin exposure is of great importance to human health. In this study, we performed the toxicological network approach to decipher AD-related mechanisms of cis-permethrin and trans-permethrin. Based on the toxicological network construction and central network topological analysis, human serum albumin (HSA) was selected as the core targets in AD-related developing. From the analysis of the steady state and time-resolved fluorescence quenching of HSA in presence of permethrin mixture, it has been inferred that the nature of the quenching mainly originates from the dynamic modes. Experimentally, the thermodynamic parameters revealed hydrophobic interactions and van der Waals forces played a major role during quenching process. Tryptophan synchronous fluorescence spectra were blue shifted whereas the position of tyrosine synchronous spectra was red shifted during the complex formation. Three-dimensional fluorescence together with FT-IR experiment confirmed that permethrin caused the secondary structure changes in HSA. To better understand the binding patterns between HSA and cis/trans -permethrin, theoretical calculation and molecular docking were implemented. According to the electrostatic potential map, the electrophilic attack region corresponds for electron rich oxygen atoms, while the nucleophilic attack regions were mainly located at over the benzene rings and methyl on cyclopropane ring of permethrins. Docking results shown that cis-permethrin and trans-permethrin located in hydrophobic pocket nearby Domain IIA with the different binding affinity (−7.6 and −9.2 kcal/mol), which consistent with the competitive displacement experiment. All these findings generated in the present study facilitated the elucidation of the molecular mechanism details between permethrin mixture and HSA, which provided fresh insights into the links between environmental exposure and AD-related adverse health outcomes.

Small molecule inhibitors of IL-1R1/IL-1β interaction identified via transfer machine learning QSAR modelling

The human interleukin-1 receptor I (IL-1R1) is a cytokine receptor recognized by interleukin 1β (IL-1β), among other cytokines. Over activation of IL-1R1 has been implicated in various inflammatory conditions. This research aims to identify small-molecule inhibitors targeting the hIL1R1/IL1β interaction, employing a multi-task transfer learning approach for quantitative structure-activity relationship (QSAR) modelling. A comprehensive bioactivity dataset from functionally related proteins was utilised to build a robust ensemble machine learning model for predicting IC50 values against the target protein. Despite the availability of antibody-based therapies, the absence of orally available small-molecule inhibitors necessitates their development. By combining model predictions with docking and simulation approaches, the interleukin-1 receptor inhibitor (IRI-1) emerged as a lead compound. It potently inhibited human IL1-R1 with micromolar activity in THP-1 and Saos-2 cells and demonstrated good biocompatibility. Western blot analysis revealed that IRI-1 inhibits IL-1β-mediated phosphorylation of IL1-R1, JNK, IRAK-4, and ERK in THP-1 cells. Furthermore, molecular dynamics simulations confirmed the structural stability of the protein-ligand complexes. This study highlights the effectiveness of multi-task transfer learning approaches for building robust QSAR models against novel proteins or those with limited bioactivity data, such as hIL-1β/IL-1R1 protein.

Investigation on X-ray diffraction, IR, UV-visible, Fluorescence, Thermogravimetric, DFT studies, and Molecular docking approach of a new C6H17.16Cl3CuN3O0.58 complex

Investigation on X-ray diffraction, IR, UV-visible, Fluorescence, Thermogravimetric, DFT studies, and Molecular docking approach of a new C6H17.16Cl3CuN3O0.58 complex

Capillary Electrophoresis-Frontal Analysis (CE-FA) and Molecular Docking Studies on the Albumin-Binding Properties of Dopamine and Serotonin.

Dopamine and serotonin are neurotransmitters that are crucial for numerous physiological processes, including mood regulation, reward, and motor function. Dysregulation of these neurotransmitters is associated with various neuropsychiatric disorders. Albumin in plasma modulates the bioavailability of drugs and free concentrations of bioactive constituents. This study aimed to characterize the interactions of dopamine and serotonin with bovine serum albumin. Capillary electrophoresis in the frontal analysis mode was utilized as an effective method to assess dopamine-bovine serum albumin and serotonin-bovine serum albumin affinity. The free neurotransmitter plateaus were distinctly separated from the bovine serum albumin-neurotransmitter complex plateaus. Free dopamine and serotonin concentrations were determined by monitoring the heights of their respective plateaus. In contrast, the bound concentrations were calculated from the difference between the total and free plateau heights. Dopamine and serotonin were found to bind to bovine serum albumin at independent sites with binding constant values of 1.90×103 and 2.90×103L/mol, respectively. Additionally, an in silico molecular docking approach revealed the binding sites for dopamine and serotonin near the glutamic acid-291 and serine-428 residues of bovine serum albumin, respectively.

Studies of the Novel Bioactive Acridine‐1,3‐thiazolidin‐4‐one Derivatives With Human Serum Albumin Using Fluorescence Spectroscopy and Molecular Modelling

ABSTRACTIn this study, we employ spectroscopic, thermodynamic and molecular docking approaches to identify the mechanism by which thiazolidinone derivatives 4a–4d bind with human serum albumin. It has been suggested that the affinity of the interaction of derivatives 4a–4d with HSA is within the optimal range necessary for the transportation and distribution of compounds within the organism. The binding constant values for the derivative/HSA complexes were found to be 0.03–5.87 × 105 M−1. Both ΔH0 and ΔS0 values were negative, which indicates that binding occurs mainly through van der Waals forces and hydrogen bonding. The negative values calculated for ΔG0 indicate that the binding of derivatives 4a–4d with HSA is a spontaneous process. Our study also reveals that derivatives 4a–4d bind to the subdomain IB (Site III) of HSA and that this binding alters the conformation and thermodynamic stability of HSA. Molecular docking simulations suggest that the main binding forces are van der Waals interactions, hydrophobic interactions and hydrogen bonds. The studied compounds showed weak DPPH‐scavenging activity at all of the tested concentrations. The results suggest that compound 4b with a phenyl substituent at the nitrogen atom of the 1,3‐thiazolidin‐4‐one moiety can be considered the most potent antioxidant in the series.

Influence of paracetamol and remdesivir association on their anti-inflammatory/antiviral efficiency: A molecular docking approach

Influence of paracetamol and remdesivir association on their anti-inflammatory/antiviral efficiency: A molecular docking approach

Studies on inhibition of α-glucosidase using debittered formulation of Bacopa monnieri juice: Enzyme inhibition kinetics, interaction strategy, and molecular docking approach

Bacopa monnieri juice (BMJ) is traditionally used, reported, and scientifically validated for memory enhancement. However, its efficacy against diabetes is less explored. The extreme bitterness of BMJ restricts its commercial applications. This study investigates the reduction of bitterness of BMJ followed by evaluation for its α-glucosidase inhibitory activity. Initially, debittering of 30 % (v/v) BMJ using ZnSO4 (15 mM) was optimized by time-intensity analysis and molecular docking of ZnSO4 as well as bacoside A3, the main active compound in BMJ, with TAS2R14 taste receptor. The study indicated 5 hydrogen bonds to be involved in binding with bacoside A3 with binding energy of −11.82 Kcal/mol, while hydrogen bond, salt bridges and metal complexes were involved in binding of ZnSO4 with binding energy of −6.65 Kcal/mol. Subsequently, BMJ, ZnSO4 and BMJ + ZnSO4 (debittered juice) were also found to be potent inhibitors of α-glucosidase in dose-dependent manner. These inhibitors showed parabolic mixed inhibition of α-glucosidase, altered the secondary structure, and quenching of fluorescence. In silico studies revealed hydrogen bonding and hydrophobic interactions between inhibitors and α-glucosidase with lowest binding energy of −15.53 and −7.54 Kcal/mol being recorded for bacoside A3 and ZnSO4, respectively. Molecular docking of other bioactive compounds in BMJ such as apigenin, luteolin, quercetin and bacopasaponin C also showed lower binding energy than the standard drug, acarbose (−5.84). This study inferred the binding of bacoside A3 at the active site of α-glucosidase and of ZnSO4 with other sites on the protein. The study proposes a debittered BMJ formulation to control hyperglycemia.

Brussonol and komaroviquinone as inhibitors of the SARS-CoV-2 Omicron BA.2 variant spike protein: A molecular docking, molecular dynamics, and quantum biochemistry approach

Since late 2019, humanity has faced the challenges posed by the COVID-19 pandemic, caused by the SARS-CoV-2 virus. The continuous evolution of SARS-CoV-2 has led to the emergence of multiple Variants of Concern (VOCs) and Variants of Interest (VOIs), posing significant risks to global health. SARS-CoV-2 infects host cells via the angiotensin-converting enzyme 2 (ACE2) receptors, facilitated by the spike (S) protein. Icetexane diterpenes, including brussonol and komaroviquinone, exhibit notable anti-inflammatory, antibacterial, antiviral, antiproliferative, and anticancer properties. Recent research has explored their potential as inhibitors of the SARS-CoV-2 3Clpro protease, showing promising efficacy comparable to Nirmatrelvir. This study investigates brussonol and komaroviquinone as potential inhibitors of the SARS-CoV-2 Omicron BA.2 variant spike protein using molecular docking, molecular dynamics simulations, and quantum biochemistry approaches. The stability and interaction energies of brussonol, komaroviquinone, and mefloquine with the SARS-CoV-2 Omicron BA.2 variant spike protein were evaluated. RMSD analysis demonstrated that komaroviquinone and mefloquine maintain more stable binding poses with the spike protein compared to various NAGs and glycans. Electrostatic potential maps revealed significant interactions with ASN603, a critical residue for ligand binding efficacy. Furthermore, this study addresses a gap in current research, as no studies were found that simulate the trimer of the SARS-CoV-2 BA.2 variant spike protein. Most existing studies focus on the monomer and often exclude the NAGs and glycans. This research underscores the importance of maintaining the NAGs and glycans in the trimer simulations, providing a more accurate representation of the protein's structure and its interactions with ligands. The findings indicate that both komaroviquinone and brussonol exhibit higher binding affinities compared to mefloquine. This study provides valuable insights into the molecular interactions of these compounds, highlighting their potential for further development as antiviral agents against SARS-CoV-2.

Interaction of molecular mechanisms of plant-derived metabolites in Type 2 diabetes mellitus: A network pharmacology, docking and molecular dynamics approach on AKT1 kinase

BackgroundT2DM is a common metabolic disease with enormous effects on health worldwide; moreover, the use of phytochemicals as therapeutic compounds has drawn increasing attention. Therefore, the objective of this study was to assess the effectiveness of these phytochemicals in combating diabetes through a comprehensive evaluation of their interactions with biological networks through network pharmacology, molecular docking, and molecular dynamics simulations. ObjectivesThe first goal of this study was to search and screen potential phytochemicals for binding with key proteins involved in T2DM, with special emphasis on AKT1 kinase, an integral component of the insulin signaling pathway. MethodsNetwork pharmacology analysis was carried out, and the interaction network of targets associated with T2DM was generated using KEGG, STRING and Cytoscape 3.9.1 software's. To determine the specific metabolic processes, cellular compartments, and molecular functions involved in T2DM, we performed Gene Ontology and KEGG analyses. An initial and short molecular docking study was conducted to analyze the binding modes, while the molecular dynamics simulations provided insights into the binding energy and stability of phytochemicals at target sites, with emphasis on rutin engaged with AKT1. ResultsIn total, 10 hub genes were proposed to be involved in T2DM and can be considered candidate therapeutic targets, namely MTOR, CASP3, CCND1, TNF, MMP9, ALB, MDM2, AKT1, and HSP90AA1. Rutin was found to have the highest binding score for AKT1 in docking studies, while MD simulations identified the structural stability and persistence of the compound's activity at the target enzyme loci. ConclusionsThis study identified rutin and flavonoids as potential anti-diabetes phytochemicals. Based on these observations, an opportunity for other in vitro experiments and additional in vivo studies to confirm these buildings as multi-target drugs in T2DM patients is provided.

From nature’s pharmacy: harnessing bioactive phytoconstituents as fibroblast growth factor receptor 3 inhibitors for anti-cancer therapeutics

Fibroblast growth factor receptor 3 (FGFR3) is a key protein involved in regulating cell growth and development. Aberrant activation of FGFR3 has been linked to several diseases, including cancer and skeletal disorders. Therefore, identifying potential inhibitors of FGFR3 is of great interest in developing targeted therapies. In this study, we employed a combined docking and molecular dynamics simulation (MDS) approach to investigate the inhibitory potential of plant-based compounds against FGFR3. Here, we utilized structure-based virtual screening to identify potential phytoconstituents from the IMPPAT library with the ability to inhibit FGFR3 activity. The initial screening process involved molecular docking to assess the binding potential of the compounds towards FGFR3. Afterward, we employed various filters to determine physicochemical properties, ADMET, and PASS evaluation to identify potential hits against FGFR3. This process discovered two phytoconstituents, Cycloartobiloxanthone and Desoxylimonin, as promising candidates against FGFR3. These compounds exhibited favorable binding affinity, efficiency, and specific interaction towards the FGFR3 binding pocket. They preferred binding to the active site of FGFR3 and possessed desirable drug-like properties. To gain a deeper understanding of their interaction mechanism, conformational dynamics, and stability, we conducted all-atom MDS lasting 200 nanoseconds (ns) on the FGFR3-Cycloartobiloxanthone and FGFR3-Desoxylimonin complexes. The MDS consistently demonstrated the formation of stable protein-ligand complexes between FGFR3 and Cycloartobiloxanthone/Desoxylimonin throughout the trajectory. Based on these results, it can be inferred that Cycloartobiloxanthone and Desoxylimonin can potentially serve as valuable scaffolds in developing drugs targeting FGFR3 for cancer therapeutic after required validation.

Identification of Anti-Tuberculosis Drugs Targeting DNA Gyrase A and Serine/Threonine Protein Kinase PknB: A Machine Learning-Assisted Drug-Repurposing Approach

Tuberculosis (TB) is a global health challenge associated with considerable levels of illness and mortality worldwide. The development of innovative therapeutic strategies is crucial to combat the rise of drug-resistant TB strains. DNA Gyrase A (GyrA) and serine/threonine protein kinase (PknB) are promising targets for new TB medications. This study employed techniques such as similarity searches, molecular docking analyses, machine learning (ML)-driven absolute binding-free energy calculations, and molecular dynamics (MD) simulations to find potential drug candidates. By combining ligand- and structure-based methods with ML principles and MD simulations, a novel strategy was proposed for identifying small molecules. Drugs with structural similarities to existing TB therapies were assessed for their binding affinity to GyrA and PknB through various docking approaches and ML-based predictions. A detailed analysis identified six promising compounds for each target, such as DB00199, DB01220, DB06827, DB11753, DB14631, and DB14703 for GyrA; and DB00547, DB00615, DB06827, DB14644, DB11753, and DB14703 for PknB. Notably, DB11753 and DB14703 show significant potential for both targets. Furthermore, MD simulations’ statistical metrics confirm the drug–target complexes’ stability, with MM-GBSA analyses underscoring their strong binding affinity, indicating their promise for TB treatment even though they were not initially designed for this disease.

Benzothiazinone analogs as Anti-Mycobacterium tuberculosis DprE1 irreversible inhibitors: Covalent docking, validation, and molecular dynamics simulations.

Mycobacterium tuberculosis is a lethal human pathogen, with the key flavoenzyme for catalyzing bacterial cell-wall biosynthesis, decaprenylphosphoryl-D-ribose oxidase (DprE1), considered an Achilles heal for tuberculosis (TB) progression. Inhibition of DprE1 blocks cell wall biosynthesis and is a highly promising antitubercular target. Macozinone (PBTZ169, a benzothiazinone (BTZ) derivative) is an irreversible DprE1 inhibitor that has attracted considerable attention because it exhibits an additive activity when combined with other anti-TB drugs. Herein, 754 BTZ analogs were assembled in a virtual library and evaluated against the DprE1 target using a covalent docking approach. After validation of the employed covalent docking approach, BTZ analogs were screened. Analogs with a docking score less than -9.0 kcal/mol were advanced for molecular dynamics (MD) simulations, followed by binding energy evaluations utilizing the MM-GBSA approach. Three BTZ analogs-namely, PubChem-155-924-621, PubChem-127-032-794, and PubChem-155-923-972- exhibited higher binding affinities against DprE1 compared to PBTZ169 with ΔGbinding values of -77.2, -74.3, and -65.4 kcal/mol, versus -49.8 kcal/mol, respectively. Structural and energetical analyses were performed for the identified analogs against DprE1 throughout the 100 ns MD simulations, and the results demonstrated the great stability of the identified BTZ analogs. Physicochemical and ADMET characteristics indicated the oral bioavailability of the identified BTZ analogs. The obtained in-silico results provide promising anti-TB inhibitors that are worth being subjected to in-vitro and in-vivo investigations.

Insights into antimalarial and anti-tuberculosis activities of Schiff base transition metal complexes: molecular docking and ADMET profiling approaches

Insights into antimalarial and anti-tuberculosis activities of Schiff base transition metal complexes: molecular docking and ADMET profiling approaches

Coupled Effect of Nutritional Food Molecules and Lactobacillus reuteri Surface Protein Interaction on the Bacterial Gastrointestinal Tolerance.

Lactobacillus reuteri, which is present in fermented foods, can produce LPxTG motif proteins (LMPs) to help the strain resist gastrointestinal fluid environmental stress and enhance the adherence and colonizing properties. Intestinal nutrient small molecules can interact with LMPs and cooperate with Lactobacillus to exert probiotic effects in the host intestine. However, the mechanism of their correlation with gastrointestinal tolerance needs to be further studied. In this study, different kinds of nutritional food molecules, such as intestinal phenols, sugars, and acids, were screened and the interaction between the LPxTG proteins and small molecules was explored via the molecular docking approach. The docking results showed that phenols and oligosaccharides were more likely to bind to the LPxTG protein (B3XKV5), with the benzene ring, phenolic hydroxyl group, and glycosidic bond in the small molecule more easily binding to the active site of B3XKV5. Furthermore, the gastrointestinal tolerance was enhanced under the rutin, myricetin, quercetin phenols, and stachyose-treated L. reuteri strain groups, especially the phenol group, which revealed the relationship between the molecular interaction of the strain with the small molecules and strain tolerance mechanism. All the findings illustrated the gastrointestinal tolerance escape effect of the Lactobacillus strain under enriched intestinal nutrient small molecular conditions, and they also provide insight regarding the small molecules for the Lactobacillus strain under abnormal growth environments.

Ginsenoside Rh4 Ameliorates Cisplatin-Induced Intestinal Toxicity via PGC-1[Formula: see text]-Mediated Mitochondrial Autophagy and Apoptosis Pathways.

Cisplatin-evoked profound gastrointestinal symptomatology is one of the most common side effects of chemotherapy drugs, causing further gastrointestinal cell and intestinal mucosal injury. Ginsenoside Rh4 (G-Rh4), an active component extracted from red ginseng, possesses beneficial anti-oxidative and anti-apoptosis effects. This study aimed to assess the effectiveness of pharmacological intervention with G-Rh4 mitigating intestinal toxicity evoked by cisplatin in a murine model and in IEC-6 cells in vitro. Following oral administration for 10 days, G-Rh4 (10[Formula: see text]mg/kg and 20[Formula: see text]mg/kg) significantly increased the indicators of diamine oxidase (DAO) affected by cisplatin (20[Formula: see text]mg/kg) in mice, and histopathological analysis further indicated that G-Rh4 could effectively improve intestinal tissue morphology, as well as the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 [Formula: see text] (PGC-1[Formula: see text] pathway and autophagy-related proteins. Moreover, in vitro experiments demonstrated that G-Rh4 exerted a concentration-dependent increase in cell viability, while also inhibiting cytotoxicity and abnormal rise of reactive oxygen species (ROS). Notably, ROS also activate PGC-1[Formula: see text] protein and mediate the occurrence of mitochondrial autophagy and apoptosis pathways. The molecular docking approach was employed to dock G-Rh4 with PGC-1[Formula: see text] and AMPK, revealing a binding energy of [Formula: see text]7.3[Formula: see text]kcal/mol and [Formula: see text]8.1[Formula: see text]kcal/mol and indicating a tight interaction between the components and the target. G-Rh4 could reduce the expression of autophagy-related protein p62/p53, reduce the accumulation of autophagy products, and promote the flow of autophagy. In conclusion, G-Rh4 exerted protective effects against cisplatin-induced intestinal toxicity, at least partially through PGC-1[Formula: see text]-mediated autophagy and apoptosis.

Exploring the Potential of Biomimetic Peptides in Targeting Fibrillar and Filamentous Alpha-Synuclein-An In Silico and Experimental Approach to Parkinson's Disease.

Alpha-synuclein (ASyn) is a protein that is known to play a critical role in Parkinson's disease (PD) due to its propensity for misfolding and aggregation. Furthermore, this process leads to oxidative stress and the formation of free radicals that cause neuronal damage. In this study, we have utilized a biomimetic approach to design new peptides derived from marine natural resources. The peptides were designed using a peptide scrambling approach where antioxidant moieties were combined with fibrillary inhibition motifs in order to design peptides that would have a dual targeting effect on ASyn misfolding. Of the 20 designed peptides, 12 were selected for examining binding interactions through molecular docking and molecular dynamics approaches, which revealed that the peptides were binding to the pre-NAC and NAC (non-amyloid component) domain residues such as Tyr39, Asn65, Gly86, and Ala85, among others. Because ASyn filaments derived from Lewy body dementia (LBD) have a different secondary structure compared to pathogenic ASyn fibrils, both forms were tested computationally. Five of those peptides were utilized for laboratory validation based on those results. The binding interactions with fibrils were confirmed using surface plasmon resonance studies, where EQALMPWIWYWKDPNGS, PYYYWKDPNGS, and PYYYWKELAQM showed higher binding. Secondary structural analyses revealed their ability to induce conformational changes in ASyn fibrils. Additionally, PYYYWKDPNGS and PYYYWKELAQM also demonstrated antioxidant properties. This study provides insight into the binding interactions of varying forms of ASyn implicated in PD. The peptides may be further investigated for mitigating fibrillation at the cellular level and may have the potential to target ASyn.