Identification and molecular mechanism of novel antioxidant peptide from fish sauce: A combined quantum chemistry and molecular simulation.

Fish sauce, derived from fermented fish, exhibits a notable antioxidant effect after a six-month fermentation process, and we propose that potential antioxidant peptides were present in the fish sauce. We isolated, purified, and identified potential bioactive antioxidant peptides by using fish sauce fermented for 6 months. Additionally, molecular simulation was employed to investigate the antioxidant action mechanism of these bioactive peptides. The molecular docking results revealed that FS4-1 (MHQLSKK), FS4-2 (VLDNSPER), FS4-3 (MNPPAASIK), FS6-1(VLKQAAAGR), and FS6-2 (SPDVSPRR), could dock with the Keap1 receptor. The primary force (Van der Waals' force and hydrogen bonds) and key sites (GLY509 and ALA510) of Keap1 binding to peptides were determined. The active center was located in the side chain of amino acid Met at positions C7H78 and C7H79. We here identified antioxidant peptides in fish sauce and revealed the antioxidant mechanism through molecular simulations.

Triazole scaffold-based DPP-IV Inhibitors for the management of Type-II Diabetes Mellitus: Insight into Molecular Docking and SAR.

Diabetes mellitus, characterized as a chronic metabolic disorder or a polygenic syndrome; is increasing at a very fast pace among every group of the population worldwide. It arises due to the inability of the body to produce enough insulin (the hormone responsible for controlling blood sugar levels) or inability to utilize the insulin, leading to hyperglycaemic condition, which, if left uncontrolled gives rise to chronic microvascular and macrovascular complications like retinopathy, neuropathy, nephropathy, coronary artery disease, cognitive impairment, etc. Several therapeutic approaches are available for the treatment of diabetes; among which dipeptidyl peptidase (DPP-IV) inhibitors (gliptins) hold a significant place. DPP-IV is a multifunctional enzyme or a serine exopeptidase that plays an imperative role in cleaving bioactive molecules. DPP-IV causes the breakdown of incretin hormone (GLP-1: Glucagon-like peptide 1 and GIP: Glucose-dependent insulinotropic peptide) that is essential for controlling glycaemic levels in the body. Inhibition of DPP-IV enzyme (DPP-IV inhibitors: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin) prevents this breakdown, thereby controlling blood glucose levels and saving the patients from deleterious effects of prolonged hyperglycaemic conditions. Triazole-based DPP-IV inhibitors are a significant class of drugs used to treat Type 2 diabetes mellitus in a dose-dependent manner. Clinical trials have demonstrated their efficacy as monotherapy or in combination with other antidiabetic agents. This review highlights the molecular docking studies and structure-activity relationship of potential synthetic derivatives that may act as lead molecules for future drug discovery and yield drug molecules with enhanced efficacy, potency and reduced toxicity profile.

Discovery of sp3-rich diazatricycloundecanes as lysosomotropic autophagy inhibitors.

We have discovered lysosomotropic autophagy inhibitors from our compound library of sp3-rich diazatricycloundecane skeletons. Compound 1u was identified as the most potent biological activity for LC3-II protein accumulation through the structure-activity relationships (SARs) for LC3-II protein accumulation and anti-proliferative activity at the three freely available substituents (R1-R3) in the diazatricycloundecane skeleton. Compound 1u inhibited lysosome-dependent degradation without affecting autophagosome formation. Furthermore, compound 1u enlarged lysosomes and raised lysosomal pH similar to lysosomotropic agents such as chloroquine, resulting in inhibiting late-stage autophagy by inducing lysosomal dysfunction. Moreover, compound 1u exhibits excellent drug-like chemical properties, not previously reported for lysosomotropic agents.

Advances in microbial exopolysaccharides as α-amylase inhibitors: Effects, structure-activity relationships, and anti-diabetic effects in vivo.

The rapid digestion of starch, as the main source of energy in the human diet, causes an acute increase in blood sugar levels that will affect blood glucose homeostasis. The inhibition of α-amylase activity is an effective way of reducing starch digestibility, thereby controlling postprandial glycemia. As a class of carbohydrate polymers, microbial exopolysaccharides (EPSs) have garnered widespread attention for their inhibitory effects on α-amylase, but there is a lack of comprehensive review in this area. This paper aimed to review the inhibitory activity of microbial EPSs on α-amylase and their interaction mechanisms, and the effect of microbial EPSs on lowering blood glucose levels and regulating glycolipid metabolism in vivo were also discussed. Numerous studies have reported that EPSs with α-amylase inhibition activity are primarily produced by lactic acid bacteria. Microbial EPSs with an appropriate range of molecular weight, high proportion of glucose or mannose or arabinose residues, and high uronic acid content might be acceptable to inhibit α-amylase activity. Additionally, microbial EPSs exhibited potential anti-diabetic effects in mice, reducing blood glucose levels, and regulating glycolipid metabolism and gut microbiota. The information covered in this review may enhance the development and application of EPSs in functional food and pharmaceutical research.

Structure-activity optimization of ryanodine receptor modulators for the treatment of catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia disorder associated with lethal arrhythmias. Most CPVT cases are caused by inherited variants in the gene encoding ryanodine receptor type 2 (RYR2). OBJECTIVE: The goal of this study was to investigate the structure-activity relationship of tetracaine derivatives and to test a lead compound in a mouse model of CPVT. METHODS: We synthesized >200 tetracaine derivatives and characterized 11 of those. The effects of these compounds on Ca2+ handling in cardiomyocytes from R176Q/+ mice was tested with confocal microscopy. The effects of lead compound MSV1302 on arrhythmia inducibility and cardiac contractility were tested by programmed electrical stimulation and echocardiography, respectively. Plasma and microsomal stability and cytotoxicity assays were also performed. RESULTS: Ca2+ imaging revealed that 3 of 11 compounds suppressed sarcoplasmic reticulum Ca2+ leak through mutant RyR2. Two compounds selected for further testing exhibited a half-maximal effective concentration of 146 nM (MSV1302) and 49 nM (MSV1406). Whereas neither compound altered baseline electrocardiogram intervals, only MSV1302 suppressed stress- and pacing-induced ventricular tachycardia in vivo in R176Q/+ mice. Echocardiography revealed that the lead compound MSV1302 did not negatively affect cardiac inotropy and chronotropy. Finally, compound MSV1302 did not block INa, ICa,L, or IKr; it exhibited excellent stability in plasma and microsomes, and it was not cytotoxic. CONCLUSION: Structure-activity relationship studies of second-generation tetracaine derivatives identified lead compound MSV1302 with a favorable pharmacokinetic profile. MSV1302 normalized aberrant RyR2 activity in vitro and in vivo, without altering cardiac inotropy, chronotropy, or off-target effects on other ion channels. This compound may be a strong candidate for future clinical studies to determine its efficacy in CPVT patients.

Plant-Derived as Alternatives to Animal-Derived Bioactive Peptides: A Review of the Preparation, Bioactivities, Structure-Activity Relationships, and Applications in Chronic Diseases.

Background/Objectives: At present, a large number of bioactive peptides have been found from plant sources with potential applications for the prevention of chronic diseases. By promoting plant-derived bioactive peptides (PDBPs), we can reduce dependence on animals, reduce greenhouse gas emissions, and protect the ecological environment. Methods: In this review, we summarize recent advances in sustainably sourced PDBPs in terms of preparation methods, biological activity, structure-activity relationships, and their use in chronic diseases. Results: Firstly, the current preparation methods of PDBPs were summarized, and the advantages and disadvantages of enzymatic method and microbial fermentation method were introduced. Secondly, the biological activities of PDBPs that have been explored are summarized, including antioxidant, antibacterial, anticancer and antihypertensive activities. Finally, based on the biological activity, the structure-activity relationship of PDBPs and its application in chronic diseases were discussed. All these provide the foundation for the development of PDBPs. However, the study of PDBPs still has some limitations. Conclusions: Overall, PDBPs is a good candidate for the prevention and treatment of chronic diseases in humans. This work provides important information for exploring the source of PDBPs, optimizing its biological activity, and accurately designing functional foods or drugs.

Design, synthesis and optimization of pyrazolo[3,4-b] pyridine derivatives as Hsp110-STAT3 interaction disruptors for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive and fatal cardiovascular disorder that is characterized by pulmonary vascular remodeling. Our previous results demonstrated that heat shock protein (Hsp110) was significantly activated to induce vascular remodeling by enhancing the Hsp110-STAT3 interaction. The development of inhibitors that disrupt this association represents a novel strategy for the treatment of PAH. This study is committed to finding new inhibitors targeting the Hsp110-STAT3 interaction based on the structure of the lead compound 2h. A fusion design principle was employed in conjunction with structural optimization in the identification of the compound 10b. In vitro data indicates that 10b exhibited greater potency in the inhibition of pulmonary vascular cells malignant phenotypes via impeding the chaperone function of Hsp110 and the Hsp110-STAT3 interaction. In hypoxia-induced PAH rats, administration of 10b significantly attenuated vascular remodeling and right ventricular hypertrophy by inhibiting the Hsp110-STAT3 association. In short, this work identified a novel and promising lead compound for the development of anti-PAH drugs targeting the Hsp110-STAT3 interaction.

Breakthroughs in AI and multi-omics for cancer drug discovery: A review.

Cancer is one of the biggest medical challenges we face today. It is characterized by abnormal, uncontrolled growth of cells that can spread to different parts of the body. Cancer is extremely complex, with genetic variations and the ability to adapt and evolve. This means we must continuously pursue innovative approaches to developing new cancer drugs. While traditional drug discovery methods have led to important breakthroughs, they also have significant limitations that make it difficult to efficiently create new, cost-effective cancer therapies. Integrating computational tools into the cancer drug discovery process is a major step forward. By harnessing computing power, we can overcome some of the inherent barriers of traditional methods. This review examines the range of computational techniques now being used, such as molecular docking, QSAR models, virtual screening, and pharmacophore modeling. It looks at recent advances in areas like machine learning and molecular simulations. The review also discusses the current challenges with these technologies and envisions future directions, underscoring how transformative these computational tools can be for creating targeted, new cancer treatments.

The general glycan profiling of Dendrobium officinale and their protective effects on MIN6 cells via ERK signaling pathway.

Based on structural elucidation of natural and hydrolyzed glycans, the general glycans profiling of D. officinale were unequivocally established for the first time as follows: The results indicated that the structure of D. officinale glycans with low degree of polymerization (DP ≤ 22) was linear α-D-1,4-glucan, whereas the structure of glycans with high degree of polymerization (DP > 24) was linear acetylated 1,4-glucomannan. The content of acetyl groups and mannose to glucose (M/G) ratio increased with the degree of polymerization of D. officinale glycans. In addition, this study showed that natural D. officinale glycans protected pancreatic ß-cell damage induced by glucotoxicity through the extracellular signal-regulated kinase (ERK)1/2 pathway.

Multifunctional Strategies of Advanced Electrocatalysts for Efficient Urea Synthesis.

The electrochemical reduction of nitrogenous species (such as N2, NO, NO2 -, and NO3 -) for urea synthesis under ambient conditions has been extensively studied due to their potential to realize carbon/nitrogen neutrality and mitigate environmental pollution, as well as provide a means to store renewable electricity generated from intermittent sources such as wind and solar power. However, the sluggish reaction kinetics and the scarcity of active sites on electrocatalysts have significantly hindered the advancement of their practical applications. Multifunctional engineering of electrocatalysts has been rationally designed and investigated to adjust their electronic structures, increase the density of active sites, and optimize the binding energies to enhance electrocatalytic performance. Here, surface engineering, defect engineering, doping engineering, and heterostructure engineering strategies for efficient nitrogen electro-reduction are comprehensively summarized. The role of each element in engineered electrocatalysts is elucidated at the atomic level, revealing the intrinsic active site, and understanding the relationship between atomic structure and catalytic performance. This review highlights the state-of-the-art progress of electrocatalytic reactions of waste nitrogenous species into urea. Moreover, this review outlines the challenges and opportunities for urea synthesis and aims to facilitate further research into the development of advanced electrocatalysts for a sustainable future.

Pyridine and Pyrimidine hybrids as privileged scaffolds in antimalarial drug discovery: A recent development.

Malaria continues to pose a significant threat to global health, which is exacerbated by the emergence of drug-resistant strains, necessitating the urgent development of new therapeutic options. Due to their substantial bioactivity in treating malaria, pyridine and pyrimidine have become the focal point of drug research. Hybrids of pyridine and pyrimidine offer a novel and promising avenue for developing effective antimalarial agents. The ability of these hybrids to overcome drug resistance is tinted, offering a potential solution to this critical obstacle in the treatment of malaria. By targeting multiple pathways, these hybrid compounds reduce the likelihood of resistance development, providing a promising strategy for combating drug-resistant strains of malaria. The review focuses on the most recent developments in 2018 in the structural optimization of pyridine and pyrimidine hybrid compounds, highlighting modifications that have been shown to improve antimalarial activity. Structure-activity studies have elucidated the essential characteristics required for potency, selectivity, and pharmacokinetics. Molecular docking and virtual screening expedite the identification of novel compounds with enhanced activity profiles. This analysis could aid in developing the most effective pyridine and pyrimidine hybrids as antimalarial agents.

Corrigendum: Deepening insights into cholinergic agents for intraocular pressure reduction: systems genetics, molecular modeling, and in vivo perspectives.

[This corrects the article DOI: 10.3389/fmolb.2024.1423351.].

Pyrrolo[2,3-d]pyrimidines as potential kinase inhibitors in cancer drug discovery: A critical review.

Pyrrolo[2,3-d]pyrimidine-based kinase inhibitors have emerged as an important class of targeted therapeutics to combat various types of cancer. The distinctive structural feature of pyrrolopyrimidine ring system offers an adaptable platform for designing potent inhibitors of various kinases, crucial in regulating cellular processes. The deazapurine framework inherent to pyrrolopyrimidines bears a conspicuous resemblance to adenine, the natural ligand ATP. The structural mimicry enhances their appeal as potent inhibitors of key kinases. This review reconnoitres the intricate process of designing and developing pyrrolopyrimidine based derivatives, accentuating their structural diversity and the strategic modifications employed to enhance selectivity, potency, and pharmacokinetic properties. The discussion delves into medicinal chemistry strategies, highlighting successful examples that have been progressed to clinical evaluation. Furthermore, the review highlights the promise of pyrrolopyrimidine scaffolds in revolutionizing targeted cancer therapy and provides a pioneering perspective on future directions.

Hidden potential of hydrazinecarboxamides (semicarbazides) as potential antimicrobial agents: A review.

Hydrazinecarboxamides (semicarbazides) are increasingly recognized as a versatile scaffold in developing potential antimicrobial agents. In addition to a brief overview of the synthetic methods to prepare them, this review comprehensively analyses their antimicrobial properties. These derivatives have demonstrated potent activity against a broad spectrum of mycobacteria, bacterial and fungal pathogens, highlighting their potential to address critical human health challenges, including neglected diseases, and to combat growing antimicrobial resistance. They have also been investigated for their antiviral and antiparasitic properties. The review also summarizes structure-activity relationships, known mechanisms of action and emphasizes the crucial role of the hydrazinecarboxamide moiety in facilitating interactions with biological targets. The combination of hydrazinecarboxamides with other bioactive scaffolds (primaquine, isoniazid, etc.) has led to an identification of promising drug candidates, including those active against resistant strains, offering a promising approach for future innovations in the field of antimicrobial therapy. Attention is also drawn to limitations of hydrazinecarboxamides (poor physicochemical properties, cytotoxicity to human cells, and insufficient target selectivity), which may hinder their clinical application.

Design, synthesis, and biological evaluation of imidazo[4,5-b]pyridine mitochondrial uncouplers for the treatment of metabolic dysfunction-associated steatohepatitis (MASH).

Small molecule mitochondrial uncouplers have gained traction for their potential therapeutic use against metabolic dysfunction-associated steatohepatitis (MASH). Herein, we report a novel imidazo[4,5-b]pyridine scaffold derived from iterative modifications of the potent uncoupler BAM15. Our structure-activity relationship (SAR) study demonstrated that this promising scaffold has a range of tolerated substitutions that allows for the modulation of uncoupling activity and in vivo pharmacokinetic properties. Specifically, compound SHS206 displayed an EC50 of 830 nM in L6 myoblasts and, importantly, showed no cytotoxicity in vitro or adverse effects in mice up to 1000 mg/kg. SHS206 was administered orally at 100 and 300 mg/kg in a GAN mouse model of MASH and was observed to lower liver triglyceride levels while food intake, body weight, temperature, organ weights, and cholesterol levels remained unaltered. Together, these findings illuminate imidazo[4,5-b]pyridine as a promising scaffold for the future development of mitochondrial uncouplers.

Analysis of implicit and explicit uncertainties in QSAR prediction of chemical toxicity: A case study of neurotoxicity.

Although uncertainties expressed in texts within QSAR studies can guide quantitative uncertainty estimations, they are often overlooked during uncertainty analysis. Using neurotoxicity as an example, this study developed a method to support analysis of implicitly and explicitly expressed uncertainties in QSAR modeling studies. Text content analysis was employed to identify implicit and explicit uncertainty indicators, whereafter uncertainties within the indicator-containing sentences were identified and systematically categorized according to 20 uncertainty sources. Our results show that implicit uncertainty was more frequent within most uncertainty sources (13/20), while explicit uncertainty was more frequent in only three sources, indicating that uncertainty is predominantly expressed implicitly in the field. The most highly cited sources included Mechanistic plausibility, Model relevance and Model performance, suggesting they constitute sources of most concern. The fact that other sources like Data balance were not mentioned, although it is recognized in the broader QSAR literature as an area of concern, demonstrates that the output from the type of analysis conducted here must be interpreted in the context of the broader QSAR literature before conclusions are drawn. Overall, the method established here can be applied in other QSAR modeling contexts and ultimately guide efforts targeted towards addressing the identified uncertainty sources.

Investigation of muscarinic acetylcholine receptor M3 activation in atomistic detail: a chemist's viewpoint.

We analyzed the precise ligand:receptor interactions required for activation of the muscarinic acetylcholine receptor M3, a prototypical G protein-coupled receptor and potential diabetes target. Starting from literature-known compounds and docking solutions, ligands were tailored for the modulation of this receptor's activation. Several aspects of the structure-activity relationship of agonists were investigated in atomistic detail, in order to delineate how the receptor can be activated via the orthosteric site. Such exquisitely precise knowledge is instrumental for designing potent and effiacious ligands. We put this strategy into practice and acquired or synthesized and measured a diverse set of 55 ligands ranging from small fragment-like amines coordinating D3.32 to bigger molecules extending towards helices 5 and 6 with diphenyl moieties. In the course of these investigations, we showed that the polarizability of the amine nitrogen and the rigidity and size of the moieties in the space delimited by helices 5 and 6 are the two key elements distinguishing potent and efficacious ligands from those that are not. The resulting data set will be highly useful in drug design and molecular machine learning alike.

Achievements and Challenges in Surfactants-Assisted Synthesis of MOFs-Derived Transition Metal-Nitrogen-Carbon as a Highly Efficient Electrocatalyst for ORR, OER, and HER.

Metal-organic frameworks (MOFs) are excellent precursors for preparing transition metal and nitrogen co-doped carbon catalysts, which have been widely utilized in the field of electrocatalysis since their initial development. However, the original MOFs derived catalysts have been greatly limited in their development and application due to their disadvantages such as metal atom aggregation, structural collapse, and narrow pore channels. Recently, surfactants-assisted MOFs derived catalysts have attracted much attention from researchers due to their advantages such as hierarchical porous structure, increased specific surface area, and many exposed active sites. This review mainly focuses on the synthesis methods of surfactants-assisted MOFs derived catalysts and comprehensively introduces the action of surfactants in MOFs derived materials and the structure-activity relationship between the catalysts and the oxygen reduction reaction, oxygen evolution reaction, and hydrogen evolution reaction performance. Apparently, the aims of this review not only introduce the status of surfactants-assisted MOFs derived catalysts in the field of electrocatalysis but also contribute to the rational design and synthesis of MOFs derived catalysts for fuel cells, metal-air cells, and electrolysis of water toward hydrogen production.

Three bioactive compounds from Huangqin decoction ameliorate Irinotecan-induced diarrhea via dual-targeting of Escherichia coli and bacterial ß-glucuronidase.

Irinotecan (CPT-11) is a commonly prescribed chemotherapeutic for the treatment of colon cancer. Unfortunately, acute and delayed diarrhea are prominent side effects of CPT-11 use, and this limits its therapeutic potential. The curative effect of Huangqin decoction (HQD) on chemotherapy-induced diarrhea has been proven. This study investigated the efficacy of the components of HQD (baicalein, baicalin, and paeoniflorin) on CPT-11-induced diarrhea and their underlying mechanisms. Baicalein was found to be the most effective component in improving CPT-11-induced enterotoxicity by intestinal permeability test, ELISA, fluorescence co-localization, and IHC. The combination of baicalin, baicalin and paeoniflorin can obtain similar therapeutic effect to that of HQD. Mendelian randomization analysis, 16 s rRNA sequencing, and fluorescence imaging revealed that baicalein and baicalin significantly inhibited ß-glucuronidase (ß-GUS) activity. Bacterial abundance analysis and scanning electron microscopy showed that baicalein inhibited the proliferation of Escherichia coli by destroying its cell wall. The molecular dynamics and site-directed mutagenesis results revealed the structural basis for the inhibition of ß-GUS by baicalein and baicalin. The results above provide a new idea for the development of drug therapy for adjuvant chemotherapy and theoretical guidance for the optimization of molecular structure targeting ß-GUS.

Structure-activity relationship of amino acid analogs to probe the binding pocket of sodium-coupled neutral amino acid transporter SNAT2.

The sodium-coupled neutral amino acid transporter SNAT2 (SLC38A2) has been shown to have important physiological functions and is implicated in various diseases like cancer. However, few compounds targeting this transporter have been identified and little is known about the structural requirements for SNAT2 binding. In this study, the aim was to establish the basic structure-activity relationship for SNAT2 using amino acid analogs. These analogs were first studied for their ability to inhibit SNAT2-mediated 3H-glycine uptake in hyperosmotically treated PC-3 cells. Then to identify substrates a FLIPR membrane potential assay and o-phthalaldehyde derivatization of intracellular amino with subsequent quantification using HPLC-Fl was used. The results showed that ester derivatives of the C-terminus maintained SNAT2 affinity, suggesting that the negative charge was less important. On the other hand, the positive charge at the N-terminus of the substrate and the ability to donate at least two hydrogen bonds to the binding site appeared important for SNAT2 recognition of the amine. Side chain charged amino acids generally had no affinity for SNAT2, but their non-charged derivatives were able to inhibit SNAT2-mediated 3H-glycine uptake, while also showing that amino acids of a notable length still had affinity for SNAT2. Several amino acid analogs appeared to be novel substrates of SNAT2, while γ-benzyl L-glutamate seemed to be inefficiently translocated by SNAT2. Elaborating on this structure could lead to the discovery of non-translocated inhibitors of SNAT2. Thus, the present study provides valuable insights into the basic structural binding requirements for SNAT2 and can aid the future discovery of compounds that target SNAT2.