Future Discovery Research Articles

Potassium channels in depression: emerging roles and potential targets

AbstractPotassium ion channels play a fundamental role in regulating cell membrane repolarization, modulating the frequency and shape of action potentials, and maintaining the resting membrane potential. A growing number of studies have indicated that dysfunction in potassium channels associates with the pathogenesis and treatment of depression. However, the involvement of potassium channels in the onset and treatment of depression has not been thoroughly summarized. In this review, we performed a comprehensive analysis of the association between multiple potassium channels and their roles in depression, and compiles the SNP loci of potassium channels associated with depression, as well as antidepressant drugs that target these channels. We discussed the pivotal role of potassium channels in the treatment of depression, provide valuable insights into new therapeutic targets for antidepressant treatment and critical clues to future drug discovery.

Structural basis of the mechanism and inhibition of a human ceramide synthase

Abstract Ceramides are bioactive sphingolipids crucial for regulating cellular metabolism. Ceramides and dihydroceramides are synthesized by six ceramide synthase (CerS) enzymes, each with specificity for different acyl-CoA substrates. Ceramide with a 16-carbon acyl chain (C16 ceramide) has been implicated in obesity, insulin resistance and liver disease and the C16 ceramide-synthesizing CerS6 is regarded as an attractive drug target for obesity-associated disease. Despite their importance, the molecular mechanism underlying ceramide synthesis by CerS enzymes remains poorly understood. Here we report cryo-electron microscopy structures of human CerS6, capturing covalent intermediate and product-bound states. These structures, along with biochemical characterization, reveal that CerS catalysis proceeds through a ping-pong reaction mechanism involving a covalent acyl–enzyme intermediate. Notably, the product-bound structure was obtained upon reaction with the mycotoxin fumonisin B1, yielding insights into its inhibition of CerS. These results provide a framework for understanding CerS function, selectivity and inhibition and open routes for future drug discovery.

Structural insights into the agonist selectivity of the adenosine A3 receptor

Adenosine receptors play pivotal roles in physiological processes. Adenosine A3 receptor (A3R), the most recently identified adenosine receptor, is expressed in various tissues, exhibiting important roles in neuron, heart, and immune cells, and is often overexpressed in tumors, highlighting the therapeutic potential of A3R-selective agents. Recently, we identified RNA-derived N6-methyladenosine (m6A) as an endogenous agonist for A3R, suggesting the relationship between RNA-derived modified adenosine and A3R. Despite extensive studies on the other adenosine receptors, the selectivity mechanism of A3R, especially for A3R-selective agonists such as m6A and namodenoson, remained elusive. Here, we identify tRNA-derived N6-isopentenyl adenosine (i6A) as an A3R-selective ligand via screening of modified nucleosides against the adenosine receptors. Like m6A, i6A is found in the human body and may be an endogenous A3R ligand. Our cryo-EM analyses elucidate the A3R-Gi complexes bound to adenosine, 5’-N-ethylcarboxamidoadenosine (NECA), m6A, i6A, and namodenoson at overall resolutions of 3.27 Å (adenosine), 2.86 Å (NECA), 3.19 Å (m6A), 3.28 Å (i6A), and 3.20 Å (namodenoson), suggesting the selectivity and activation mechanism of A3R. We further conduct structure-guided engineering of m6A-insensitive A3R, which may aid future research targeting m6A and A3R, providing a molecular basis for future drug discovery.

Chromosome architecture as a determinant for biosynthetic diversity in Micromonospora.

Natural products - small molecules generated by organisms to facilitate ecological interactions - are of great importance to society and are used as antibacterial, antiviral, antifungal and anticancer drugs. However, the role and evolution of these molecules and the fitness benefits they provide to their hosts in their natural habitat remain an outstanding question. In bacteria, the genes that encode the biosynthetic proteins that generate these molecules are organised into discrete loci termed biosynthetic gene clusters (BGCs). In this work, we asked the following question: How are biosynthetic gene clusters organised at the chromosomal level? We sought to answer this using publicly available high-quality assemblies of Micromonospora, an actinomycete genus with members responsible for biosynthesizing notable natural products, such as gentamicin and calicheamicin. By orienting the Micromonospora chromosome around the origin of replication, we demonstrated that Micromonospora has a conserved origin-proximal region, which becomes progressively more disordered towards the antipodes of the origin. We then demonstrated through genome mining of these organisms that the conserved origin-proximal region and the origin-distal region of Micromonospora have distinct populations of BGCs and, in this regard, parallel the organization of Streptomyces, which possesses linear chromosomes. Specifically, the origin-proximal region contains highly syntenous, conserved BGCs predicted to biosynthesize terpenes and a type III polyketide synthase. In contrast, the ori-distal region contains a highly diverse population of BGCs, with many BGCs belonging to unique gene cluster families. These data highlight that genomic plasticity in Micromonospora is locus-specific, and highlight the importance of using high-quality genome assemblies for natural product discovery and guide future natural product discovery by highlighting that biosynthetic novelty may be enriched in specific chromosomal neighbourhoods.

Full-Body Impressions: A category of trace fossils unique to exceptionally preserved bedding planes and indicators of true substrates

Certain biogenic sedimentary structures can be considered to be reliable indicators of true substrates. Full-body impressions, or FBIs, are trace fossils that are shallow, highly-detailed impressions of the ventral axial anatomy of low body mass animals made while living . Their mode of preservation makes FBIs distinct from undertracks, body moulds, or passive tool marks. FBIs are made at the air- or water-substrate interface during sedimentary stasis. Associated trace fossils, like those that exhibit excavations with preserved waste mounds and very near-surface burrow roofs, located on the same bedding plane, can support the interpretation of true substrate preservation. Integration of the biogenic and sedimentological data from both Carboniferous and Pleistocene sites with well-preserved bedding-plane trace fossil assemblages has confirmed the conditions under which true substrates are preserved. These include periods (as brief as days to weeks) of sedimentary stasis, followed by gentle deposition without erosion, and without the need to invoke biofilms or biomats as consolidants. The potential for these taphonomic conditions exist in both alluvial and lacustrine environments, as well as intertidal-estuarine valleys, as described by other published examples of FBI preservation. Future FBI discoveries will prove useful in identifying true substrates across a range of time periods and environments.

L858R/L718Q and L858R/L792H Mutations of EGFR Inducing Resistance Against Osimertinib by Forming Additional Hydrogen Bonds.

Acquired resistance to first-line treatments in various cancers both promotes cancer recurrence as well as limits effective treatment. This is true for epidermal growth factor receptor (EGFR) mutations, for which secondary EGFR mutations are one of the principal mechanisms conferring resistance to the covalent inhibitor osimertinib. Thus, it is very important to develop a deeper understanding of the secondary mutational resistance mechanisms associated with EGFR mutations arising in tumors treated with osimertinib to expedite the development of innovative therapeutic drugs to overcome acquired resistance. This work uses all-atom molecular dynamics (MD) simulations to investigate the conformational variation of two reported EGFR mutants (L858R/L718Q and L858R/L792H) that resist osimertinib. The wild-type EGFR kinase domain and the L858R mutant are used as the reference. Our MD simulation results revealed that both the L718Q and L792H secondary mutations induce additional hydrogen bonds between the residues in the active pocket and the residues with the water molecules. These additional hydrogen bonds reduce the exposure area of C797, the covalent binding target of osimertinib. The additional hydrogen bonds also influence the binding affinity of the EGFR kinase domain by altering the secondary structure and flexibility of the amino acid residues in the domain. Our work highlights how the two reported mutations may alter both residue-residue and residue-solvent hydrogen bonds, affecting protein binding properties, which could be helpful for future drug discovery.

Physics, AI, and the future of discovery

Leaders from industry, government, and academia discuss the potential impact of AI on physics—including neutrinos, exoplanets, term papers, outreach, and workforce gaps—and of physics on AI.

The influence of parasitic modes on stable lattice Boltzmann schemes and weakly unstable multi-step Finite Difference schemes

Numerical analysis for linear constant-coefficient multi-step Finite Difference schemes is a longstanding topic, developed approximately fifty years ago. It relies on the stability of the scheme, and thus—within the L2 setting—on the absence of multiple roots of the amplification polynomial on the unit circle. This allows for the decoupling, while discussing the convergence of the method, of the study of the consistency of the scheme from the precise knowledge of its parasitic/spurious modes, so that the methods can be essentially studied as if they had only one step. Furthermore, stability alleviates the need to delve into the complexities of floating-point arithmetic on computers, which can be challenging topics to address. In this paper, we demonstrate that in the case of “weakly” unstable Finite Difference schemes with multiple roots on the unit circle, although the schemes may remain stable, considering parasitic modes is essential in studying their consistency and, consequently, their convergence. This research was prompted by unexpected numerical results on stable lattice Boltzmann schemes, which can be rewritten in terms of multi-step Finite Difference schemes. Unlike Finite Difference schemes, rigorous numerical analysis for lattice Boltzmann schemes is a contemporary topic with much left for future discoveries. Initial expectations suggested that third-order initialization schemes would suffice to maintain the accuracy of fourth-order schemes. However, this assumption proved incorrect for weakly unstable Finite Difference schemes and for stable lattice Boltzmann methods. This borderline scenario underscores that particular care must be adopted for lattice Boltzmann schemes, and the significance of genuine stability in facilitating the construction of Lax-Richtmyer-like theorems and in mastering the impact of round-off errors concerning Finite Difference schemes. Despite the simplicity and apparent lack of practical usage of the linear transport equation at constant velocity considered throughout the paper, we demonstrate that high-order lattice Boltzmann schemes for this equation can be used to tackle nonlinear systems of conservation laws relying on a Jin-Xin approximation and high-order splitting formulæ.

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.

Elucidating Antibiotic Permeation through the Escherichia coli Outer Membrane: Insights from Molecular Dynamics.

Antibiotic resistance represents a critical public health threat, with an increasing number of Gram-negative pathogens demonstrating resistance to a broad range of clinical drugs. A primary challenge in enhancing antibiotic efficacy is overcoming the robust barrier presented by the bacterial outer membrane. Our research addresses a longstanding question: What is the rate of antibiotic permeation across the outer membrane (OM) of Gram-negative bacteria? Utilizing molecular dynamics (MD) simulations, we assess the passive permeability profiles of four commercially available antibiotics─gentamicin, novobiocin, rifampicin, and tetracycline across an asymmetric atomistic model of the Escherichia coli (E. coli) OM, employing the inhomogeneous solubility-diffusion model. Our examination of the interactions between these drugs and their environmental context during OM permeation reveals that extended hydrogen bond formation and drug-cation interactions significantly hinder the energetics of passive permeation, notably affecting novobiocin. Our MD simulations corroborate well with experimental data and reveal new implications of solvation on drug permeability, overall advancing the possible use of computational prediction of membrane permeability in future antibiotic discovery.

Exploring the Cosmos: Impact and Significance of the James Webb Space Telescope

The James Webb Space Telescope (JWST) marks a pivotal advancement in astronomical research, building upon the legacy of its predecessors by enhancing the observational capabilities and expanding the understanding of the universe. This study explores the transformative impact of JWST, emphasizing its role in studying the formation and evolution of early galaxies, stars, and planetary systems. By utilizing its advanced infrared capabilities, JWST can penetrate cosmic dust and observe celestial phenomena that were previously obscured, thereby providing unprecedented insights into the early universe and the origins of life’s building blocks. The findings from JWST are expected to challenge existing theories and assumptions in cosmology and astrophysics, facilitating a paradigm shift in the comprehension of cosmic structures and the fundamental processes governing them. Furthermore, the telescope’s ability to analyze exoplanetary atmospheres will contribute significantly to the search for life beyond Earth. Ultimately, the JWST not only represents a technological marvel but also serves as a cornerstone for future astronomical discoveries, shaping the conception of the cosmos for generations to come.

In silico-guided synthesis of a new, highly soluble, and anti-melanoma flavone glucoside: Skullcapflavone II-6'-O-β-glucoside.

Guided by in silico analysis tools and biotransformation technology, new derivatives of natural compounds with heightened bioactivities can be explored and synthesized efficiently. In this study, in silico data mining and molecular docking analysis predicted that glucosides of skullcapflavone II (SKII) were new flavonoid compounds and had higher binding potential to oncogenic proteins than SKII. These benefits guided us to perform glycosylation of SKII by utilizing four glycoside hydrolases and five glycosyltransferases (GTs). Findings unveiled that exclusive glycosylation of SKII was achieved solely through the action of GTs, with Bacillus subtilis BsUGT489 exhibiting the highest catalytic glycosylation efficacy. Structure analysis determined the glycosylated product as a novel compound, skullcapflavone II-6'-O-β-glucoside (SKII-G). Significantly, the aqueous solubility of SKII-G exceeded its precursor, SKII, by 272-fold. Furthermore, SKII-G demonstrated noteworthy anti-melanoma activity against human A2058 cells, exhibiting an IC50 value surpassing that of SKII by 1.4-fold. Intriguingly, no substantial cytotoxic effects were observed in a murine macrophage cell line, RAW 264.7. This promising anti-melanoma activity without adverse effects on macrophages suggests that SKII-G could be a potential candidate for further preclinical and clinical studies. The in silico tool-guided synthesis of a new, highly soluble, and potent anti-melanoma glucoside, SKII-G, provides a rational design to facilitate the future discovery of new and bioactive compounds.

Thermal Quenching Mechanism of Mn4+ in Na2SiF6, NaKSiF6, and K2SiF6 Phosphors: Insights from the First-Principles Analysis.

This study aims to identify the key factors governing the thermal quenching of Mn4+ ion luminescence in fluoride-based phosphor materials used as red emitters in modern-day phosphor-converted LED devices. Here, we employ first-principles calculations for Mn4+-doped Na2SiF6, NaKSiF6, and K2SiF6 hosts to explore how host properties and local coordination environments influence thermal quenching behavior. The ΔSCF method was used to model the geometric structures of the Mn4+4A2 (ground) and 2E, 4T2 (excited) states and the energies of the optical transitions between these states. Our results reveal that thermal quenching in Na2SiF6 and K2SiF6 phosphors occurs through thermally activated 2E → 4T2 → 4A2 crossover. In contrast, thermal quenching in NaKSiF6 is due to other nonradiative decay pathways. Investigations of the mechanical stability of these fluorides show that NaKSiF6 is mechanically unstable. We suggest that this property of the host limits the luminescence efficiency of the embedded Mn4+ ions. We also determined the reason for the difference in the intensity of the 2E → 4A2 emission transition (ZPL) in the systems. These findings advance our fundamental understanding of the thermal quenching mechanism of Mn4+ ion luminescence in fluorides, and the results can aid future discoveries of technologically useful phosphors through high-throughput design methodologies.

Orphan GPCRs in Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches.

Neurodegenerative disorders, particularly Alzheimer's and Parkinson's diseases, continue to challenge modern medicine despite therapeutic advances. Orphan G-protein-coupled receptors (GPCRs) have emerged as promising targets in the central nervous system, offering new avenues for drug development. This review focuses on the structural biology of orphan GPCRs implicated in these disorders, providing a comprehensive analysis of their molecular architecture and functional mechanisms. We examine recent breakthroughs in structural determination techniques, such as cryo-electron microscopy and X-ray crystallography, which have elucidated the intricate conformations of these receptors. The review highlights how structural insights inform our understanding of orphan GPCR activation, ligand binding and signaling pathways. By integrating structural data with molecular pharmacology, we explore the potential of structure-guided approaches in developing targeted therapeutics toward orphan GPCRs. This structural-biology-centered perspective aims to deepen our comprehension of orphan GPCRs and guide future drug discovery efforts in neurodegenerative disorders.

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.

Exploring voltage-gated sodium channel conformations and protein-protein interactions using AlphaFold2.

Voltage-gated sodium (Na V ) channels are vital regulators of electrical activity in excitable cells, playing critical roles in generating and propagating action potentials. Given their importance in physiology, Na V channels are key therapeutic targets for treating numerous conditions, yet developing subtype-selective drugs remains challenging due to the high sequence and structural conservation among Na V family members. Recent advances in cryo-electron microscopy have resolved nearly all human Na V channels, providing valuable insights into their structure and function. However, limitations persist in fully capturing the complex conformational states that underlie Na V channel gating and modulation. This study explores the capability of AlphaFold2 to sample multiple Na V channel conformations and assess AlphaFold Multimer's accuracy in modeling interactions between the Na V α-subunit and its protein partners, including auxiliary β-subunits and calmodulin. We enhance conformational sampling to explore Na V channel conformations using a subsampled multiple sequence alignment approach and varying the number of recycles. Our results demonstrate that AlphaFold2 models multiple Na V channel conformations, including those from experimental structures, new states not yet experimentally identified, and potential intermediate states. Furthermore, AlphaFold Multimer models Na V complexes with auxiliary β-subunits and calmodulin with high accuracy, and the presence of protein partners significantly alters the conformational landscape of the Na V α-subunit. These findings highlight the potential of deep learning-based methods to expand our understanding of Na V channel structure, gating, and modulation, with significant implications for future drug discovery efforts.

A review of virus host factor discovery using CRISPR screening.

The emergence of genome-scale forward genetic screening techniques, such as Haploid Genetic screen and clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen has opened new horizons in our understanding of virus infection biology. CRISPR screening has become a popular tool for the discovery of novel host factors for several viruses due to its specificity and efficiency in genome editing. Here, we review how CRISPR screening has revolutionized our understanding of virus-host interactions from scientific and technological viewpoints. A summary of the published screens conducted thus far to uncover virus host factors is presented, highlighting their experimental design and significant findings. We will outline relevant methods for customizing the CRISPR screening process to answer more specific hypotheses and compile a glossary of conducted CRISPR screens to show their design aspects. Furthermore, using flaviviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as examples, we hope to offer a broad-based perspective on the capabilities of CRISPR screening to serve as a reference point to guide future unbiased discovery of virus host factors.

Family Malvaceae: a potential source of secondary metabolites with chemopreventive and anticancer activities supported with in silico pharmacokinetic and pharmacodynamic profiles.

Cancer is the second most widespread cause of mortality following cardiovascular disorders, and it imposes a heavy global burden. Nowadays, herbal nutraceutical products with a plethora of bioactive metabolites represent a foundation stone for the development of promising chemopreventive and anticancer agents. Certain members of the family Malvaceae have traditionally been employed to relieve tumors. The literature concerning the chemopreventive and anticancer effects of the plant species along with the isolated cytotoxic phytometabolites was reviewed. Based on the findings, comprehensive computational modelling studies were performed to explore the pharmacokinetic and pharmacodynamic profiles of the reported cytotoxic metabolites to present basis for future plant-based anticancer drug discovery. All the available information about the anticancer research in family Malvaceae and its cytotoxic phytometabolites were retrieved from official sources. Extensive search was carried out using the keywords Malvaceae, cancer, cytotoxicity, mechanism and signalling pathway. Pharmacokinetic study was performed on the cytotoxic metabolites using SWISS ADME model. Acute oral toxicity expressed as median lethal dose (LD50) was predicted using Pro Tox 3.0 web tool. The compounds were docked using AutoDock Vina platform against epidermal growth factor receptor (EGFR kinase enzyme) obtained from the Protein Data Bank. Molecular dynamic simulations and MMGBSA calculations were performed using GROMACS 2024.2 and gmx_MMPBSA tool v1.5.2. One hundred forty-five articles were eligible in the study. Several tested compounds showed safe pharmacokinetic properties. Also, the molecular docking study showed that the bioactive metabolites possessed agreeable binding affinities to EGFR kinase enzyme. Tiliroside (25), boehmenan (30), boehmenan H (31), and isoquercetin (22) elicited the highest binding affinity toward the enzyme with a score of -10.4, -10.4, -10.2 and -10.1Kcal/mol compared to the reference drug erlotinib having a binding score equal to -9Kcal/mol. Additionally, compounds 25 and 31 elicited binding free energies equal to -42.17 and -42.68Kcal/mol, respectively, comparable to erlotinib. Overall, the current study presents helpful insights into the pharmacokinetic and pharmacodynamic properties of the reported cytotoxic metabolites belonging to family Malvaceae members. The molecular docking and dynamic simulations results intensify the roles of secondary metabolites from medicinal plants in fighting cancer.

Exploring the Antidiabetic Potential of Salvia officinalis Using Network Pharmacology, Molecular Docking and ADME/Drug-Likeness Predictions.

A combination of network pharmacology, molecular docking and ADME/drug-likeness predictions was employed to explore the potential of Salvia officinalis compounds to interact with key targets involved in the pathogenesis of T2DM. These were predicted using the SwissTargetPrediction, Similarity Ensemble Approach and BindingDB databases. Networks were constructed using the STRING online tool and Cytoscape (v.3.9.1) software. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis and molecular docking were performed using DAVID, SHINEGO 0.77 and MOE suite, respectively. ADME/drug-likeness parameters were computed using SwissADME and Molsoft L.L.C. The top-ranking targets were CTNNB1, JUN, ESR1, RELA, NR3C1, CREB1, PPARG, PTGS2, CYP3A4, MMP9, UGT2B7, CYP2C19, SLCO1B1, AR, CYP19A1, PARP1, CYP1A2, CYP1B1, HSD17B1, and GSK3B. Apigenin, caffeic acid, oleanolic acid, rosmarinic acid, hispidulin, and salvianolic acid B showed the highest degree of connections in the compound-target network. Gene enrichment analysis identified pathways involved in insulin resistance, adherens junctions, metabolic processes, IL-17, TNF-α, cAMP, relaxin, and AGE-RAGE in diabetic complications. Rosmarinic acid, caffeic acid, and salvianolic acid B showed the most promising interactions with PTGS2, DPP4, AMY1A, PTB1B, PPARG, GSK3B and RELA. Overall, this study enhances understanding of the antidiabetic activity of S. officinalis and provides further insights for future drug discovery purposes.

Promising tools for future drug discovery and development in antiarrhythmic therapy.

Arrhythmia refers to irregularities in the rate and rhythm of the heart, with symptoms spanning from mild palpitations to life-threatening arrhythmias and sudden cardiac death (SCD). The complex molecular nature of arrhythmias complicates the selection of appropriate treatment. Current therapies involve the use of antiarrhythmic drugs (class I-IV) with limited efficacy and dangerous side effects and implantable pacemakers and cardioverter-defibrillators with hardware-related complications and inappropriate shocks. The number of novel antiarrhythmic drug in the development pipeline has decreased substantially during the last decade and underscores uncertainties regarding future developments in this field. Consequently, arrhythmia treatment poses significant challenges, prompting the need for alternative approaches. Remarkably, innovative drug discovery and development technologies show promise in helping advance antiarrhythmic therapies. Here, we review unique characteristics and the transformative potential of emerging technologies that offer unprecedented opportunities for transitioning from traditional antiarrhythmics to next-generation therapies. We assess stem cell technology, emphasizing the utility of innovative cell profiling using multi-omics, high-throughput screening, and advanced computational modeling in developing treatments tailored precisely to individual genetic and physiological profiles. We offer insights into gene therapy, peptide and peptibody approaches for drug delivery. We finally discuss potential strengths and weaknesses of such techniques in reducing adverse effects and enhancing overall treatment outcomes, leading to more effective, specific, and safer therapies. Altogether, this comprehensive overview introduces innovative avenues for personalized rhythm therapy, with particular emphasis on drug discovery, aiming to advance the arrhythmia treatment landscape and the prevention of SCD. Significance Statement Arrhythmias and sudden cardiac death account for 15-20% of deaths worldwide. However, current antiarrhythmic therapies are ineffective and with dangerous side effects. Here, we review the field of arrhythmia treatment underscoring the slow progress in advancing the cardiac rhythm therapy pipeline and the uncertainties regarding evolution of this field. We provide information on how emerging technological and experimental tools can help accelerate progress and address the limitations of antiarrhythmic drug discovery.