Search Results (955)

The Bactericidal action of β-lactam antibiotics is related to covalent modification of transpeptidases, enzymes that take part in the synthesis of bacterial cell wall. The β-lactam moiety mimics the transpeptidase substrate and irreversibly inhibits the enzyme. In penicillin and cephalosporin, the β-lactam ring is coupled with a five-membered thiazolidine ring or a six-membered dihydrothiazine ring, respectively. In the case of penicillins, such conjunction causes higher tension of this bicyclic moiety; therefore, the β-lactam ring can be hydrolyzed in certain conditions, inactivating the antibiotic. Serum albumin is known for its drug binding capabilities, which enable it to transport pharmaceuticals through the circulatory system. Penicillins and cephalosporins are no exception in this aspect, and they are also carried by serum albumin in the bloodstream. In this study, we structurally investigate the ability of three serum albumins—equine (ESA), caprine (CSA), and ovine (OSA)—to bind two penicillins, ampicillin (Amp) and oxacillin (Oxa), and two cephalosporins, cefaclor (Cef) and cephalosporin C (Csc). The crystal structures of these mammalian serum albumin complexes shed new light on the albumin binding properties of β-lactam antibiotics, showing one common binding site for Amp, Oxa, and Cef in Fatty Acid Site 6 (FA6), and a second cefaclor molecule bound in domain I of the equine serum albumin. It was surprising that these antibiotics are not bound in the main drug binding site. However, cephalosporin C is bound in OSA Drug Site 1 (DS1). Full article

Deep eutectic solvents are a sustainable and chemically tunable class of solvents formed by strong hydrogen bonding between a hydrogen bond acceptor and a hydrogen bond donor. Their extreme versatility has established deep eutectic solvents in ten key applied areas, including the green extraction of bioactive compounds, CO₂ capture, electrochemistry, and the catalytic media. Research is shifting towards highly innovative frontier trends, such as the role of deep eutectic solvents in dynamic covalent chemistry and as templates for advanced photocatalytic nanomaterials. Other innovative directions include artificial organelles for bioremediation, thermoacoustic deep eutectic solvents for smart drug delivery, and their use as multifunctional interfaces for 2D materials. The future of deep eutectic solvents lies in process engineering and scale-up, supported by computational chemistry, confirming their position as a central pillar of the circular economy. This trajectory marks the transition of deep eutectic solvents from laboratory curiosities to a scalable industrial reality. Full article

Background/Objectives: Discriminating bacterial from mammalian membranes remains a central challenge in antibiotic design. Bacterial membranes are enriched in phosphatidylethanolamine (PE), a lipid normally absent from the outer leaflet of mammalian cells, providing a signature for selective molecular engagement. We report a compact covalent ligand, 6-dimethylamino-4-ketohexanoic acid (DMAX), which targets PE via Schiff base formation, leveraging its tertiary amine to facilitate the reaction and strengthen ionic binding with the phosphate group. Methods: The reactivity of DMAX and PE was evaluated by computational simulations, and their interaction was examined by spectroscopic analyses (NMR and FT-IR) and an artificial membrane assay. The targeting ability of DMAX for live bacteria was determined by microscopy study, and its applicability to therapeutic system was tested in vitro under washed conditions that mimic rapid in vivo clearance. Results: Spectrometric analyses revealed the selective covalent interaction of DMAX and PE, consistent with the simulated results. Fluorescently labeled DMAX selectively binds PE-enriched model membranes and efficiently recognizes Gram-negative bacteria while sparing mammalian cells. Conjugation of DMAX to Gemifloxacin (Gem) significantly enhanced antibiotic efficacy by 10-fold compared with free Gem, even after rapid drug clearance, while maintaining safety in mammalian cells. Conclusions: These results identify DMAX as an efficient and versatile PE-targeting platform, enabling selective membrane anchoring to advance precision antibiotic strategies. Full article

This study reports the development of paclitaxel (PTX)-loaded human serum albumin (HSA) nanoparticles (NPs), surface-decorated with trastuzumab (TMAB), with potential applicability in HER2-oriented delivery. The NPs were obtained via thermally driven self-assembly followed by non-covalent antibody adsorption and they were characterized using Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and ζ-potential analysis. The drug association efficiency (%DAE), defined exclusively for PTX, was high for both HSA-PTX and HSA-PTX-TMAB NPs (96.4% and 98.2% w/w, respectively), with loading capacities (%LC) of 8.9% and 7.4%, respectively. TMAB decoration led to a modest increase in mean diameter and a reduction in surface charge, consistent with successful surface modification. Both formulations exhibited rapid early-phase PTX release followed by an apparent stabilization phase, with distinct kinetic behavior between HSA–PTX and HSA–PTX–TMAB NPs. Cytotoxicity in A549 cells after 18 h of exposure showed modest, non-differential effects consistent with controlled release and short-term assessment of non-specific toxicity. Overall, this thermally assembled albumin-based system provides a promising foundation for further evaluation of HER2-oriented PTX delivery. Full article

Arabinoxylans (AX) are polysaccharides capable of forming covalent gels stable under variations in pH and temperature. They are fermentable by the colonic microbiota, making them appropriate carriers for colon-targeted oral drug delivery, including insulin. This study aimed to fabricate covalent AX nanoparticles loaded with insulin (NPAXI) using a 0.25 (AX/insulin) mass ratio and to evaluate their colon-targeted capacity to improve glycemic control in diabetic rats. In parallel, we assessed gut microbiota modulation as a secondary outcome, derived from the prebiotic fermentation of AX, considered an additional benefit. NPAXI, produced by coaxial electro spraying, displayed a mean diameter of 661 nm, a zeta potential of −31 mV, and high insulin encapsulation efficiency. Bioassay demonstrated that a single oral NPAXI dose restored normoglycemia for 9 h, starting 15 h post-administration. Gut microbiota analysis revealed that while insulin alone increased Lactobacillaceae, it failed to suppress Enterobacteriaceae. NPAXI treatment, however, promoted beneficial taxa such as Muribaculaceae and Prevotellaceae and reduced proinflammatory families like Desulfovibrionaceae and Helicobacteraceae. These microbial shifts paralleled the improved glycemic profile, suggesting a synergistic interaction between AX and insulin in reestablishing gut microbial homeostasis and metabolic regulation. Overall, NPAXI represents a promising strategy for colon-targeted oral insulin delivery, offering additional microbiota-modulating benefits. Full article

Dynamic covalent hydrogels exhibiting multi-responsive and antibacterial properties offer significant potential for biomedical applications, including smart wound dressings and controlled drug delivery. Herein, a series of amphiphilic quaternized copolymers (Q-C8PEG-n) with tunable quaternization degrees was synthesized from C8PEG via iodomethane addition and characterized by ¹H NMR, COSY, FTIR, UV-vis spectroscopy, DLS, TEM, and zeta potential analyses, confirming successful quaternization and micelle formation. These copolymers displayed thermosensitive behavior, with cloud point temperatures increasing due to enhanced hydrophilicity. Q-C8PEG-3 micelles, incorporating diethanolamine units, were crosslinked with phenylboronic acid-grafted hyaluronic acid (HA-PBA) to yield dynamic covalent hydrogels (Gel) through reversible boronic ester bonds stabilized by B-N coordination. The Gel exhibited multi-responsiveness, undergoing degradation in acidic or alkaline conditions and exposure to glucose or H₂O₂. SEM confirmed a porous microstructure, enabling efficient drug encapsulation, as demonstrated by the release of Nile red (NR). In vitro antibacterial tests revealed enhanced post-quaternization efficacy, with the Gel showing strong activity against S. aureus. This micelle-crosslinked platform synergistically combines tunable stimuli-responsiveness with inherent antibacterial properties, holding promise for applications in wound healing and tissue engineering. Full article

Magnetic microrobots have emerged as a promising platform for drug delivery in recent years. By enabling remotely controlled motion and precise navigation under external magnetic fields, these systems offer new solutions to overcome the limitations of traditional drug delivery nanocarriers, such as inadequate tissue penetration and heterogeneous biodistribution. Over the past few years, significant advancements have been made in the structural design of magnetic microrobots, as well as in drug loading techniques and stimuli-responsive drug release mechanisms, thereby demonstrating distinct advantages in enhancing therapeutic efficacy and targeting precision. This review provides a comprehensive overview of magnetic drug delivery microrobots, which are categorised into biomimetic structural, bio-templated and advanced material-based types, and introduces their differences in propulsion efficiency and biocompatibility. Additionally, drug loading and release strategies are summarised, including physical adsorption, covalent coupling, encapsulation, and multistimuli-responsive mechanisms such as pH, enzyme activity and thermal triggers. Overall, these advancements highlight the significant potential of magnetic microrobots in targeted drug delivery and emphasise the key challenges in their clinical translation, such as biological safety, large-scale production and precise targeted navigation within complex biological environments. Full article

Vanillin (4-hydroxy-3-methoxybenzaldehyde) is widely recognized for its aromatic flavor and established pharmacological properties, including antioxidant, antimicrobial, anti-inflammatory, and anticancer effects. While these biological activities underpin its therapeutic potential, recent advances have expanded the application of vanillin into the field of biomaterials. In particular, vanillin’s unique chemical structure enables its use as a multifunctional building block for the development of innovative hydrogels with dynamic covalent bonding, injectability, and self-healing capabilities. Vanillin-based hydrogels have demonstrated promising applications in wound healing, drug delivery, tissue engineering, and antimicrobial platforms, combining structural support with intrinsic bioactivity. These hydrogels benefit from vanillin’s biocompatibility and functional versatility, enhancing mechanical properties and therapeutic efficacy. This review provides an overview of vanillin’s pharmacological effects, with a primary focus on the synthesis, properties, and biomedical applications of vanillin-derived hydrogels. By highlighting recent material innovations and their translational potential, we aim to position vanillin as a valuable natural compound bridging bioactivity and biomaterial science for future clinical and therapeutic advancements. Full article

Pyrimethamine (PYR), a drug approved for the treatment of infections caused by protozoan parasites, is a multifunctional API based on 2,4-diaminopyrimidine scaffold. The present study aims toward the development of novel solid forms of PYR, by combining it with three isomeric aminobenzoic acids—2-aminobenzoic acid (2NH₂-BA), 3-aminobenzoic acid (3NH₂-BA), and 4-aminobenzoic acid (4NH₂-BA). Solution crystallization led to the formation of three new solvated salts of PYR (PYR/2NH₂-BA/EtOH/H₂O, PYR/3NH₂-BA/EtOH, and PYR/4NH₂-BA/EtOH/H₂O). The detailed physicochemical properties of the formed compounds were characterized by single-crystal X-ray diffraction (SC-XRD), FTIR, PXRD, thermogravimetry (TG), and differential scanning calorimetry (DSC). Additionally, the pre-crystallization solutions of PYR with 2NH₂-BA, 3NH₂-BA, and 4NH₂-BA were studied by electrospray ionization mass spectrometry technique (ESI-MS), which enabled the observation of peaks corresponding to noncovalently bonded molecules, providing insight into their specific aggregation in a solution/gas phase environment. We identified different non-covalent aggregates, including self-aggregates of aminobenzoic acids and PYR/aminobenzoic acid associates of different stoichiometries. Full article

Temperature-responsive hydrogels are sophisticated stimuli-responsive biomaterials that undergo rapid, reversible sol–gel phase transitions in response to subtle thermal stimuli, most notably around physiological temperature. This inherent thermosensitivity enables non-invasive, precise spatiotemporal control of material properties and bioactive payload release, rendering them highly promising for advanced biomedical applications. This review critically surveys recent advances in the design, synthesis, and translational potential of thermo-responsive hydrogels, emphasizing nanoscale and hybrid architectures optimized for superior tunability and biological performance. Foundational systems remain dominated by poly(N-isopropylacrylamide) (PNIPAAm), which exhibits a sharp lower critical solution temperature near 32 °C, alongside Pluronic/Poloxamer triblock copolymers and thermosensitive cellulose derivatives. Contemporary developments increasingly exploit biohybrid and nanocomposite strategies that incorporate natural polymers such as chitosan, gelatin, or hyaluronic acid with synthetic thermo-responsive segments, yielding materials with markedly enhanced mechanical robustness, biocompatibility, and physiologically relevant transition behavior. Cross-linking methodologies—encompassing covalent chemical approaches, dynamic physical interactions, and radiation-induced polymerization are rigorously assessed for their effects on network topology, swelling/deswelling kinetics, pore structure, and degradation characteristics. Prominent applications include on-demand drug and gene delivery, injectable in situ gelling systems, three-dimensional matrices for cell encapsulation and organoid culture, tissue engineering scaffolds, self-healing wound dressings, and responsive biosensing platforms. The integration of multi-stimuli orthogonality, nanotechnology, and artificial intelligence-guided materials discovery is anticipated to deliver fully programmable, patient-specific hydrogels, establishing them as pivotal enabling technologies in precision and regenerative medicine. Full article

In this study, new improved inhibitors of the viral enzyme 3-chymotrypsin-like protease (3CL^pro) were designed using structure-based drug design techniques in an effort to discover more effective treatment of coronavirus disease 2019 (COVID-19). Three-dimensional models of 3CL^pro–inhibitor complexes were prepared by in situ modification of the crystal structure of the submicromolar covalent inhibitor IPCL6 for a set of 25 known inhibitors with published inhibitory potencies (${IC}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$). The QSAR model was prepared with a reasonable correlation between the calculated free energies of formation of the 3CL^pro-IPCL complex (∆∆G_com) and the experimentally determined activities ${IC}_{50}^{\mathrm{e}\mathrm{x}\mathrm{p}}$, which explained approximately 92% of the variation in the 3CL^pro inhibition data. A similar agreement was achieved for the QSAR pharmacophore model (PH4) built on the basis of the active conformations of the IPCL inhibitors bound at the active site of the 3CL^pro. The virtual combinatorial library of more than 567,000 IPCL analogues was screened in silico using the PH4 model and resulted in the identification of 39 promising analogues. The best inhibitors designed in this study show high predicted affinity for the 3CL^pro protease, as well as favourable predicted ADME properties. For the best new virtual inhibitor candidate IPCL 80-27-74-4, the inhibitory concentration ${IC}_{50}^{\mathrm{p}\mathrm{r}\mathrm{e}}$ was predicted equal to 0.8 nM, which represents a significant improvement in the inhibitory potency of known IPCLs. Ultimately, molecular dynamics simulations of the 12 newly designed top-scoring IPCL inhibitors demonstrated that the 3CL^pro–inhibitor complexes exhibited good structural stability, confirming the potential for further development of the designed IPCL analogues. Full article

Background/Objectives: Microtubule-targeting agents remain foundational components of anticancer chemotherapy, yet their clinical utility is constrained by resistance and toxicity. Methods: Here, we present a theoretical exploration of a plausible “dual” binding pocket that spans the α-tubulin pironetin site and the inter-subunit todalam site. Eight virtual chimeric ligands, each merging key pharmacophoric elements of pironetin and todalam, were constructed and covalently docked to Cys316 of α-tubulin. Results: Covalent docking followed by 200 ns all-atom molecular dynamics simulations revealed that two derivatives (compounds 4 and 8) stably occupy the merged cavity, simultaneously anchoring in the pironetin region via Michael addition and in the todalam region via π-stacking and hydrogen bonding. These hybrids preserved the critical hydrogen-bonding networks of both parent ligands and exhibited low ligand RMSD values (~1.5 Å) and compact radii of gyration throughout the simulations, indicating a tight, persistent binding. Estimated HYDE affinities of 1.5 µM for compound 4 and 17.6 µM for compound 8, calculated with SeeSAR, suggest that covalent engagement can compensate for moderate non-covalent binding scores. Conclusions: In summary, our results provide compelling grounds for developing a new class of α-tubulin inhibitors that engage the hybrid pocket, laying a foundation for the structure-guided synthesis of first-in-class dual-site compounds capable of overcoming resistance to conventional microtubule-targeting drugs. Full article

Activity-based protein profiling (ABPP) has emerged as a powerful chemical proteomics approach for profiling active amino acid residues, mapping functional proteins, and guiding covalent drug development in complex biological systems. Recent methodological advances have produced several novel formats, including tandem orthogonal proteolysis-ABPP (TOP-ABPP), isotopic tandem orthogonal proteolysis-ABPP (IsoTOP-ABPP), and competitive IsoTOP-ABPP, enabling broader target identification and quantitative analysis for varied experimental purposes. In parallel, chemical probe design has evolved to selectively target specific amino acid residues, such as cysteine (Cys), lysine (Lys), and histidine (His), and to incorporate photoaffinity labeling (PAL) functionalities for capturing transient or weak protein-ligand interactions. Additionally, the integration of cleavable linkers with diverse cleavage mechanisms, including acid/base-mediated, redox-mediated, and photo irradiation mechanisms, has enhanced probe versatility and downstream analytical workflows. This review summarizes recent advances in ABPP methodologies and the design of activity-based probes and PAL probes, emphasizing their implications for future work in chemical biology. Full article

Artificial neural networks in drug discovery have shown remarkable potential in various areas, including molecular similarity assessment and virtual screening. This study presents a novel multimodal Siamese neural network architecture. The aim was to join molecular electrostatic potential (MEP) images with the texture features derived from reduced density gradient (RDG) diagrams for enhanced molecular similarity prediction. On one side, the proposed model is combined with a convolutional neural network (CNN) for processing MEP visual information. This data is added to the multilayer perceptron (MLP) that extracts texture features from gray-level co-occurrence matrices (GLCM) computed from RDG diagrams. Both representations converge through a multimodal projector into a shared embedding space, which was trained using triplet loss to learn similarity and dissimilarity patterns. Limitations associated with the use of purely structural descriptors were overcome by incorporating non-covalent interaction information through RDG profiles, which enables the identification of bioisosteric relationships needed for rational drug design. Three datasets were used to evaluate the performance of the developed model: tyrosine kinase inhibitors (TKIs) targeting the mutant T315I BCR-ABL receptor for the treatment of chronic myeloid leukemia, acetylcholinesterase inhibitors (AChEIs) for Alzheimer’s disease therapy, and heterodimeric AChEI candidates for cross-validation. The visual and texture features of the Siamese architecture help in the capture of molecular similarities based on electrostatic and non-covalent interaction profiles. Therefore, the developed protocol offers a suitable approach in computational drug discovery, being a promising framework for virtual screening, drug repositioning, and the identification of novel therapeutic candidates. Full article

Background/Objectives: Dihydroquercetin (DHQ), also known as taxifolin, is a natural flavonoid which has anti-inflammatory and wound-healing biological effects. One of the main limitations for developing formulations with DHQ is its low solubility in water at room temperature. One of the high-potential co-formers for increasing its solubility is l-lysine, which has an aliphatic amino group in the side radical capable of entering into intermolecular interactions with the phenolic hydroxyl groups of DHQ. Methods: Several modifications were obtained using grinding, drying, and lyophilization methods. Subsequent evaluation was conducted using a combination of physicochemical and biological analytical methods. Results: Obtained modifications could be described as very easily soluble substances. The absence of the formation of new covalent bonds between the compounds during the formation of such systems was established. The glass transition effect was detected at 64 °C for the obtained films. It is important to note that as a result of studying the cytotoxic properties of the objects, a decrease in cytotoxicity was established during lyophilization of the mechanical mixture of the initial components. For these lyophilizates, the IC50 value was 0.025 mg/mL, 0.068 mg/mL, 0.145 mg/mL, and 0.288 mg/mL for the 3T3, HEK293, Caco-2, and HUVEC cell lines, respectively. Conclusions: Co-amorphous systems of DHQ and l-lysine in the form of films and lyophilizates were obtained and described. These objects may be interesting from the point of view of increasing the solubility of natural flavonoids, which solves one of the main problems in developing drugs based on them. Full article