Search Results (614)

Significant advances in coronavirus immunoprophylaxis have enabled the control of the SARS-CoV-2 pandemic. However, the continued emergence of SARS-CoV-2 variants with immune escape potential highlights the need for effective direct-acting antivirals targeting conserved viral enzymes. The SARS-CoV-2 main protease (M^pro) remains one of the most promising antiviral drug targets due to its essential role in viral replication and the high conservation of its active site across coronavirus variants. Building upon the established GC373 scaffold, we designed, synthesized, and biochemically evaluated two novel GC373-like peptidomimetic inhibitors incorporated modified glutamine-mimic residues. These analogs were designed to enhance solubility and metabolic resilience while retaining key recognition features within the M^pro active site. Both compounds demonstrated micromolar inhibitory activity in enzymatic assays, supported by molecular docking and MM-PBSA analyses consistent with stable binding. The proposed inhibitors represent viable scaffolds for further optimization of electrophilic warheads and S1/S2 residue interactions. These findings contribute to the rational design of next-generation M^pro inhibitors and align with ongoing efforts to expand the chemical space of SARS-CoV-2 antiviral agents. Full article

The global space economy, valued at approximately USD 400–630 billion (depending on definitional scope), is projected to expand rapidly, crossing USD 1 trillion as early as 2032 and reaching up to about USD 1.8 trillion by 2035. This growth has been driven by a surge (a roughly twelvefold increase) in satellite launches over the past decade, transforming Earth’s orbits into an increasingly congested domain plagued by space debris. The proliferation of space junk poses an escalating threat to orbital sustainability, yet effective governance mechanisms remain limited. This paper examines why conventional solutions for managing common-pool resources (command-and-control regulation, Pigouvian taxes, private property rights, allocation of tradable permits, and horizontal governance regimes) are not fully effective or are difficult to implement in addressing the orbital debris problem. Using a system dynamics perspective, the study qualitatively maps hypothesized feedback mechanisms shaping orbital expansion and space debris accumulation. It suggests that, under the assumed causal structure, reinforcing growth loops associated with geopolitical rivalry and commercial cost reductions linked to the New Space paradigm currently dominate over delayed balancing effects arising from the finite nature of orbital space, whose regenerative capacity is progressively degraded. There exists a threshold of exploitation beyond which orbital space effectively behaves as a non-renewable resource. The analysis suggests that, without binding international coordination, meaningful intervention may require the occurrence of a catalyzing crisis—e.g., a localized cascade of orbital object collisions that could transform stakeholder perceptions and enables active debris removal deployment. Full article

The origin of life embodies two fundamental questions: how and when did life begin? It is commonly conjectured that life began on Earth around 4 billion years ago. This requires that the complex organization of RNA, DNA, triplet codon, protein, and lipid membrane (RDTPM) architecture was easy to establish between the time the Earth cooled enough for liquid water and the time when early microorganisms appeared. These bracketing events create a narrow window of time to construct a completely operational self-replicating organic system of very high complexity. Another conjecture is that life did not begin on Earth but was seeded from life-bearing space objects (e.g., asteroids, comets, space dust), commonly referred to as panspermia. The second conjecture implies that life formed somewhere else and was part of the solar nebula, originating from an earlier generation star where there was more time available for the development of life. In this paper, the goal is to provide a hypothetical perspective related to the timing for the origin of pre-biotic chemistry and life itself. Using a form of complexity growth, biological features spanning from the present day back to early life on Earth were examined for trends across time. Genome sizes, gene number, protein–protein binding sites, energy for cell construction, mass of individual cells, the rate of cell mass growth, and a molecular complexity measure all yield highly significant regressions of linearly increasing complexity when plotted over the last 4 Gyr (billion years). When extrapolated back in time, intersections with simple complexities associated with each variable yield a mean value of 8.6 Gyr before the present time. This era coincides with the peak of star and planet formation in the universe. This speculative analysis is consistent with the second conjecture for the origin of life. The major assumptions of such an analysis are presented and discussed. Full article

Coordination polymers (CPs) are garnering attention in the field of medicine day by day. The goal is to develop a CP with biosafe and environment-friendly characteristics. Herein, we report two such novel 3D coordination polymers of zinc-inosine-5′-monophosphate (Zn-IMP) and bpe/azpy (as linkers) which were engineered as metal–organic frameworks that can be used as drug carriers for hydroxyurea (HU). We employed SCXRD, PXRD, solid-state CD, FTIR and TGA for crystal structure characterizations; the results achieved 3D coordination polymers which contain a P2₁ space group with chiral distorted tetrahedral geometry. Solution phase studies like UV–vis and CD were carried out to understand mechanistic pathways for interaction and chirality, respectively. We have also performed computational studies to evaluate the drug delivery capacity of both 3D CPs. Molecular docking and multi-pH molecular dynamics (MD) quantify that HU binds more strongly with CP−1 (ΔG =−10.87 ± 0.12) as compared to CP−2 (ΔG = −7.59 ± 0.26 kcal·mol⁻¹), at normal and basic pH. MD simulation analysis indicated that a more compact and rigid cavity is observed by CP−1 as compared to CP−2 at physiological pH. Across acidic pH, for CP−1 the ligand RMSD increases markedly and U becomes slightly less negative, which indicated partial loss of contacts, thus releasing drugs in a tumor-like environment more easily. These result showed that CP−1 offers stronger binding, higher structural stability and a more pronounced pH-responsive release profile than CP−2, making CP-1 more promising candidate for targeted HU drug delivery, while CP−2 may serve as a weaker-binding, faster-release complement. Full article

Rb₂KWO₃F₃ elpasolite was synthesized via the solid-state reaction route. The phase purity of the obtained sample was verified by the XRD analysis with Rietveld refinement in space group Fm-3m, yielding the unit cell parameter a = 8.92413 (17) Å. The electronic structure and chemical states of the constituent elements were investigated using X-ray photoelectron spectroscopy. The binding energy of the W 4f_7/2 core level (34.95 eV) was found to be characteristic of the W⁶⁺ oxidation state, while the values for Rb 3d, K 2p, O 1s and F 1s levels were consistent with those reported for related oxide and oxyfluoride compounds. First-principles density functional theory calculations were performed to model the electronic structure. The fac-configuration of the WO₃F₃ octahedra was identified as the most energetically favorable. The calculations revealed a direct band gap of 4.38 eV, with the valence band maximum composed primarily of O 2p orbitals and the conduction band minimum formed by W 5d orbitals. This combined experimental/theoretical study shows that the electronic structure and wide bandgap of Rb₂KWO₃F₃ are governed by the WO₃F₃ units and are largely insensitive to the Rb/K substitution. The wide bandgap identifies this class of oxyfluorides as a promising platform for developing new UV-transparent materials. Full article

The renin–angiotensin–aldosterone system (RAAS) is essential for controlling blood pressure and maintaining fluid balance, driving significant structural changes throughout the cardiovascular system, including the heart and blood vessels. As a result, the RAAS is a key therapeutic target for various chronic cardiovascular diseases, ranging from arterial hypertension (AH) to heart failure (HF). In this review, one of our objectives is to describe the new evidence over the last 4 years regarding the RAAS. Moreover, we pay attention to the structure and function of the angiotensin II type 1 receptor (AT1R) and its role in hypertension, as well as define its active site. Later, we discuss the most potent, selective inhibitors of AT1 receptors, based on in vitro and in vivo experiments, from 2020 to 2024. Large peptide molecules, small non-peptide-like molecules, and sartan derivatives are analyzed. The low IC₅₀ values of the entities that do not resemble sartans showcase the vast chemical space that can be explored for the creation of more potent antihypertensive medications. We have also employed computational chemistry tools in order to identify key molecular interactions between the compounds of the literature studied in order to elucidate the underlying reasons why these different molecules exhibit variations in their binding energies and overall potency. Full article

Proteomes are typically analyzed at the level of individual proteins or protein families. In this study, we introduce a bottom-up approach that treats proteomes as holistic entities by examining the properties of k-mers within entire proteomes and protein groups. We performed a comprehensive analysis of short amino acid k-mer (k = 1, 2, 3) distributions across all proteins in a given proteome. Using 86 bacterial proteomes representing 18 clades, we evaluated whether k-mer frequencies characterize uniquely the analyzed organisms. Remarkably, in a post hoc analysis, we found that the k-mer frequency vector unambiguously coevolves with the entire proteome—a pattern not observed even within specific protein groups, such as conserved ribosomal proteins or more variable nucleotide-binding proteins. This finding holds regardless of the k-mer calculation parameters or the distance metrics employed. Our results show that even a simple analysis based on tripeptide frequencies can precisely position proteomes within the k-mer space. Moreover, relationships derived from k-mer comparisons highly correlate with evolutionary relationships derived from phylogenetic trees, reaching up to 99% match with reference classification of the proteomes within major bacterial clades. These findings establish k-mer-based proteomic analysis as an additional robust and powerful feature for characterizing evolutionary relationships, opening new pathways in phylogenetics and evolutionary genomics. Full article

Nominally weakly coordinating anions are useful for modulating the solubility and chemical properties of metal complexes, but identification and analysis of the systematics of the interactions of anions with cationic metal complexes has not received the attention it deserves. Here, a chemical informatics approach is demonstrated for identifying and quantitatively analyzing the ways that the bis(trifluoromethylsulfonyl)imide anion (TFSI) can interact with metal-containing species. An open access computer program (PyCIFTer) was developed to facilitate large-scale structural analysis of TFSI-containing species by utilization of experimental atomic coordinate data from single-crystal X-ray diffraction (XRD) studies obtained from the Cambridge Structural Database (CSD). PyCIFTer establishes a three-dimensional vector space from the raw atomic coordinates, generating acyclic, undirected graphs that are used to rapidly analyze the structural properties (bond lengths and angles) of TFSI in individual structures in sequential/batch fashion. The structures are sorted by PyCIFTer into groups based on pre-set and chemically sensible criteria, affording a comprehensive and systematic view of TFSI structural chemistry. This approach avoids tedious one-at-a-time interrogation of structures, a prospect unreasonable in this case, and many others of contemporary chemical relevance; there were over 1500 structures in the CSD containing TFSI as of November 2024. The results demonstrate that TFSI only rarely binds to cations in the solid state, favoring the formation of species in which TFSI is found in cations’ outer coordination spheres. The prospect of applying PyCIFTer to other moieties is also discussed. PyCIFTer is also schematically compared to the commercial CSD Python application programming interface (API). Taken together, this work demonstrates the usefulness of modular workflows for sequential/batch analysis of structural data from XRD, an approach that appears poised to accelerate the translation of legacy structural results into new chemical insights and hypotheses. Full article

With the in-depth development of digital twin technology in modern agriculture, smart pig farm construction is evolving from basic environmental modeling toward refined, bio-behavior-driven approaches. This study addresses the non-standard body configurations and complex behavioral patterns of pig models by proposing a binding method that combines lightweight skeletal design with automated weight allocation strategies. The method optimizes skeletal layout schemes based on pig physiological structures and behavioral patterns, replacing manual painting processes through geometry-driven weight calculation strategies to achieve a balance between efficiency and animation naturalness. The research constructs a motion template library containing common behaviors such as walking and foraging, conducting quantitative testing and comprehensive evaluation in simulation systems. Experimental results demonstrate that the proposed method achieves significant improvements: it demonstrated superior computational efficiency with 95.2% reduction in computation time, memory storage space reduced by 91.7% through weight matrix sparsification (density controlled at 8.3%), and weight smoothness was maintained at 0.955 while cross-region weight leakage reduced from 15.3% to 2.1%. The method effectively supports animation expression of eight typical pig behavioral patterns with key joint angle errors controlled within 2.3 degrees, providing a technically viable and economically feasible pathway for virtual modeling and intelligent interaction in smart agriculture. Full article

Background: Osteoarthritis (OA) is a chronic degenerative whole joint disease characterized by cartilage breakdown and inflammation. Galectin-3 (Gal-3), a β-galactoside-binding lectin secreted into the extracellular space, binds to glycosylated components of the extracellular matrix (ECM), modulating cell–matrix interactions and inflammation. This study aims to evaluate the anti-inflammatory effects of Hylach^®, a hyaluronic acid (HA) derivative conjugated with lactose-based residues that bind Gal-3, on in vitro inflamed primary human chondrocytes. Methods: Chondrocyte viability, after both Hylach^® and HA treatments at different concentrations was assessed using the MTT assay. Two-dimensional and 3D cell cultures exposed to the conditioned medium (CM) of activated U937 monocytes and subsequently treated with Hylach or HA, were analyzed for the expression of IL-1β, IL-6, TNF-α, and Gal-3 at different time points (4, 10, and 24 h). Results: HA and Hylach^® did not affect cell viability at any of the tested concentrations. Both molecules reduced the overexpression of Gal-3 and pro-inflammatory molecules in 2D inflamed cell cultures, at both gene and protein levels. Notably, IL-1β, IL-6 and Gal-3 showed a more pronounced inhibitory effect at 4 h, with Hylach demonstrating a stronger reduction compared to native HA. Moreover, in inflamed 3D chondrocyte cultures, Hylach^® but not HA, significantly reduced IL-1β, TNF-α and Gal-3 gene expression. Conclusions: Hylach^® exerts an early and more potent anti-inflammatory effect in inflamed 2D and 3D chondrocyte cultures when compared to HA. These findings suggest that targeting Gal-3 through selective HA derivatives may represent a promising strategy for modulating both inflammation and matrix remodelling in OA. Full article

The Colorado potato beetle (CPB) is the primary defoliator of potatoes and is notorious for its ability to develop resistance to various insecticides. This remarkable adaptability may partly reflect selective pressures imposed due to the beetle’s coevolution with toxic Solanaceous host plants. As the initial interface between the environment and the insect olfactory system, odorant-binding proteins (OBPs) may sequester excess harmful molecules, such as insecticides and plant allelochemicals, in the perireceptor space, mitigating deleterious effects on vulnerable olfactory sensory neuronal dendrites. In this study, we identified an antenna-specific OBP (LdecOBP33) that is significantly upregulated in a pesticide resistant strain compared to a susceptible one. Competitive displacement fluorescence binding assays demonstrated that the LdecOBP33 protein exhibited broad affinity toward a range of plant volatiles and insecticides. Silencing LdecOBP33 decreased the beetle’s resistance to imidacloprid and impaired its ability to locate host plants. Together, these findings provide insight into a key molecular factor involved in the CPB’s response to environmental challenges, suggesting a potential link between insects’ adaptation to xenobiotics and their olfactory processing. Full article

Objectives: One of the major trends in modern computational toxicology is the development of explainable predictive tools. However, the complex nature of the mechanistic representation of biological organisms and the lack of relevant data remain limiting factors. Methods: This work provides a publicly available dataset of 12,654 compounds with mouse intravenous ${\mathrm{LD}}_{50}$ values, as well as docking scores (Vina-GPU 2.0) against 44 toxicity-associated proteins. NIH and Brenk filters were applied to refine the chemical space. Results: Across the entire protein panel, the human ether-a-go-go–related gene channel (hERG/KCNH2), vasopressin receptor 1A (AVPR1A), the L-type voltage-gated calcium channel Cav1.2 (CACNA1C), the potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) and endothelin receptor A (EDNRA) showed the strongest association with acute toxicity. Statistically significant differences were found in the distribution of ${\mathrm{LD}}_{50}$ values for compounds that bind antitargets compared with non-binders. Using known bioactive molecules such as anisodamine, butaperazine, soman, and several cannabinoids as examples confirmed the effectiveness of inverse docking for elucidating mechanism of action. Conclusions: The dataset offers a resource to advance transparent, mechanism-aware toxicity modeling. The data is openly available. Full article

The complex relationship between urban torrents and riparian communities is investigated in this research, from a landscape point of view, in the aftermath of the catastrophic floods in Volos, Greece, in September 2023. The study starts with a multi-scalar approach, investigating through plural timescales and space-scales the way communities and torrents have co-existed in the Mediterranean; particularly in Volos, the way neoteric urban infrastructures have affected and underestimated torrentscapes, is observed critically. This investigation extends to the legislative spatial planning framework in Greece and the EU, concerning the torrent-beds and torrentscapes, in the framework of extreme climate events brought about by climate change. Highlighting the dual challenges of floods and droughts, the research uncovers the inadequacy of existing gray infrastructure and of top-down management approaches, in addressing flood risk. Co-vulnerability emerges as a binding agent, between riparian communities and torrent ecosystems. By the means of research-by/through-design in synergy with anthropological research tools, this approach aims at fostering “just” resilience, by presupposing social justice, towards the promotion of Integrated - Catchment- Management- Plans -(ICMPs) that combine the mitigation of flood risk and extreme drought challenges, the enhancement of torrentscape ecosystems, and the strengthening of the symbiotic relationship between the city inhabitants and its torrents. Full article

Helicobacter pylori urease (HpU) plays a central role in bacterial survival and virulence by hydrolyzing urea into ammonia and carbon dioxide, neutralizing gastric acidity, and facilitating host colonization. The increasing prevalence of antibiotic resistance underscores the need for alternative strategies targeting essential bacterial enzymes such as urease. In this study, a multistage computational pipeline integrating pharmacophore modeling, machine learning (ML), ensemble docking, and enhanced molecular dynamics simulations were applied to identify novel triazole-based HpU inhibitors. Starting from over seven million compounds in the ZINC15 database, pharmacophore- and ML-based filters progressively reduced the chemical space to 7062 candidates. Ensemble docking across 25 conformational frames of HpU, followed by quantum-polarized ligand docking (QPLD), identified seven promising ligands exhibiting strong binding energies and stable metal coordination. Molecular dynamics (MD) simulations under progressively relaxed restraints revealed three highly stable complexes (CA1, CA3, and CA6). Subsequent well-tempered metadynamics (WT-MetaD) simulations reconstructed free-energy landscapes showing deep, localized basins for CA3 and CA6, comparable to the potent reference inhibitor DJM, supporting their potential as strong urease binders. Finally, unsupervised chemical space mapping using the UMAP algorithm positioned these candidates within molecular regions associated with potent urease inhibitors, further validating their structural coherence and pharmacophoric relevance. An ADMET assessment confirmed that the selected candidates exhibit physicochemical and early safety properties compatible with subsequent in vitro evaluation. This multilevel screening strategy demonstrates the power of combining ML-driven classification, ensemble docking, and enhanced sampling simulations to discover non-hydroxamic urease inhibitors. Although the current findings are computational, they provide a rational foundation for future in vitro validation and for expanding the discovery of triazole-based scaffolds targeting ureolytic enzymes. Full article

Background/Objectives: Vector-borne diseases like malaria remain a major global health concern, worsened by insecticide resistance in mosquito populations. Quinoline-based compounds have been extensively studied for their pharmacological effects, including antimalarial and larvicidal properties. Modifying quinoline structures with hydrazone groups may enhance their biological activity and physicochemical properties. This study reports the synthesis, structural characterization, and larvicidal testing of a new series of aryl hydrazones (6a–i) derived from 8-trifluoromethyl quinoline. Methods: Compounds 6a–i were prepared via condensation reactions and characterized using ¹H NMR, ¹⁹F-NMR, ¹³C NMR, and HRMS techniques. Their larvicidal activity was tested against Anopheles arabiensis. Single-crystal X-ray diffraction (XRD) was performed on compound 6d to determine its three-dimensional structure. Hirshfeld surface analysis, fingerprint plots, and interaction energy calculations (HF/3-21G) were used to examine intermolecular interactions. Quantum chemical parameters were computed using density functional theory (DFT). Molecular docking studies were performed for the synthesized compounds 6a–i against the target acetylcholinesterase from the malaria vector (6ARY). In silico ADMET properties were also calculated to evaluate the drug-likeness of all the tested compounds. Results: Compound 6a showed the highest larvicidal activity, causing significant mortality in Anopheles arabiensis larvae. Single-crystal XRD analysis of 6d revealed a monoclinic crystal system with space group P2₁/c, stabilized by N–H···N intermolecular hydrogen bonds. Hirshfeld analysis identified H···H (22.0%) and C···H (12.1%) interactions as key contributors to molecular packing. Density functional theory results indicated a favorable HOMO–LUMO energy gap, supporting molecular stability and good electronic distribution. The most active compounds, 6a and 6d, also showed strong binding interactions with the target protein 6ARY and satisfactory ADMET properties. The BOILED-Egg model is a powerful tool for predicting both blood–brain barrier (BBB) and gastrointestinal permeation by calculating the lipophilicity and polarity of the reported compounds 6a–i. Conclusions: The synthesized arylhydrazone derivatives demonstrated promising larvicidal activity. Combined crystallographic and computational studies support their structural stability and suitability for further development as eco-friendly bioactive agents in malaria vector control. Full article