Search Results (195)

TiO₂–carbon nanotube (TiO₂–CNT) hybrids are promising gas-sensor platforms because they combine the chemically active and photoresponsive surface of TiO₂ with the high conductivity and interfacial sensitivity of CNT networks. Yet cross-study comparison remains difficult because materials, device architectures, humidity, activation modes, and response definitions vary widely. This comprehensive review connects interfacial mechanisms and architectures with performance benchmarking and design rules. Direct gas-sensing evidence is distinguished from supporting interfacial studies and contextual analogues. We assess band alignment, oxygen vacancies, CNT functionalization, shell thickness, percolation, photoactivation, humidity, and analyte-specific behavior across NO_x, NH₃, H₂, H₂S, VOCs, LPG, O₂, and humidity sensing. The evidence shows that response is governed more strongly by interface continuity, spatial location, and the dominant current pathway than by nominal composition alone. Thin conformal coatings, discrete oxide decoration, and interpenetrating networks can each be advantageous; none is universally superior. Because response definitions and protocols remain inconsistent, we propose a benchmarking framework separating response magnitude from sensitivity, kinetics, selectivity, stability, humidity robustness, and activation requirements. These relationships yield practical design rules for controlling receptor chemistry, interface quality, percolation, activation energy, and validation conditions, providing a route from proof-of-concept demonstrations toward reproducible, low-power, application-relevant TiO₂–CNT gas sensors. Full article

Peptide engineering has emerged as a powerful strategy to optimize naturally occurring peptides. Here, the amphibian skin peptide Hp-1891 from Boana pulchella was selected as a model scaffold to investigate the effects of two complementary engineering approaches, namely site-specific D-amino acid substitution and head-to-tail cyclization. A library of twelve analogues was synthesized by 9-fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase peptide synthesis and evaluated for inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro), together with antioxidant and hemolytic activities. Circular dichroism spectroscopy and molecular modeling were performed to investigate the structural basis of the observed biological effects. Head-to-tail cyclization consistently enhanced inhibition of AChE, BChE, and Mpro, whereas D-amino acid substitution exerted a greater influence on antioxidant activity and hemolysis. Among the analogue library, c-Hp-d2 emerged as the most promising multifunctional peptide, displaying enhanced inhibition of all three enzymes while maintaining reduced hemolytic activity compared with the native peptide. Structural analyses indicated that cyclization promoted conformational organization, whereas D-amino acid incorporation reduced α-helical propensity. These findings demonstrate that rational peptide engineering effectively reshapes the biological profile of amphibian peptides and highlight head-to-tail cyclization as a versatile strategy for generating multifunctional peptide scaffolds with therapeutic potential. Full article

Background/Objectives: Antimicrobial peptides (AMPs) have emerged as promising alternatives to conventional antibiotics in response to the escalating global threat of antimicrobial resistance (AMR), owing to their potent antimicrobial activity and low propensity for resistance development. However, their clinical application remains limited by poor selectivity and undesirable toxicity toward mammalian cells. Methods: In this study, the naturally occurring frog-derived AMP Dermaseptin-A4 (A4) was selected as a template for rational design. Guided by the principle that optimising the balance between peptide hydrophobicity and cationicity could improve bacterial membrane targeting while reducing interactions with mammalian membranes, three analogues were designed through the targeted modulation of these physicochemical properties. Results: Among the designed analogues, A4-3 exhibited the best overall biological profile. A4-3 maintained a stable α-helical conformation in membrane-mimicking environments and displayed potent antimicrobial activity against tested Gram-positive and Gram-negative bacteria while exhibiting lower haemolytic and cytotoxic effects than the parent peptide. As a result, A4-3 showed improved selectivity, achieving a selectivity index of up to 34.5. A4-3 rapidly eradicated bacterial cells through a membrane-targeting mechanism, leading to membrane disruption and the loss of cellular integrity, and exhibited a low propensity for resistance development following prolonged exposure. A4-3 also retained its antimicrobial activity under physiologically relevant conditions. Conclusions: Collectively, these findings demonstrate that achieving an optimal balance between peptide hydrophobicity and cationicity is an effective strategy for enhancing antimicrobial selectivity without compromising antibacterial activity, highlighting A4-3 as a promising lead candidate for the development of novel antimicrobial therapeutics against drug-resistant bacterial infections. Full article

The rapid emergence of antimicrobial resistance necessitates the development of novel antimicrobial agents with improved efficacy and selectivity. In this study, a dermatoxin-like peptide, dermatoxin-PD1, was identified from the skin secretion of Pachymedusa dacnicolor, and its structure–activity relationship was investigated through a rational truncation strategy based on predicted proteolytic cleavage sites. A series of truncated analogues was generated, among which a shortened peptide fragment (T1) retained potent antimicrobial activity, particularly against Gram-negative bacteria, whereas further truncation resulted in a marked loss of function. Structural analysis revealed that both dermatoxin-PD1 and T1 adopted amphipathic α-helical conformations under membrane-mimicking conditions. Functional assays demonstrated that bacterial killing was associated with membrane permeabilisation and depolarisation, with additional evidence supporting interactions with lipopolysaccharide (LPS). Notably, T1 exhibited remarkably reduced haemolytic and cytotoxic effects compared with the parent peptide, resulting in an improved selectivity profile. These findings provide additional insight into the structure–activity relationship of dermatoxin-like peptides and suggest that protease cleavage-guided truncation may represent a useful strategy for developing shorter and safer antimicrobial peptides. Full article

Heterocyclic unnatural amino acids and their biheterocyclic derivatives represent invaluable structural scaffolds in modern medicinal chemistry and peptidomimetics due to their ability to induce conformational constraints and modulate pharmacokinetic profiles. While saturated nitrogen heterocycles and monocycle heteroaromatic systems are well-established pharmacophores, research on linear biheterocyclic amino acid frameworks remains significantly underrepresented in the literature. Addressing this structural gap, this study aims to synthesize and characterize a novel series of functionalized pyrimidine (hetero)cyclic molecular hybrids acting as chiral heterocyclic amino acid derivatives. The target pyrimidine-5-carboxylates and pyrimidine-4-carboxylic acid derivatives were prepared from β-dicarbonyl compounds and their corresponding enamine analogues via cyclocondensation approaches. Particular attention was paid to reaction optimization, substrate scope exploration, and stereochemical integrity preservation, utilizing chiral HPLC analysis to evaluate enantiomeric retention. Pyrimidine-5-carboxylates prepared from β-enamino keto esters retained high enantiomeric excess (90.2–100% ee), whereas cyclization of β-diketones under strongly basic conditions at elevated temperature resulted in complete racemization (ee < 1%). Modification of the synthetic route and application of milder cyclization conditions partially suppressed racemization, affording pyrimidine derivatives with 61.8–65.5% ee. These findings suggest that substrate structure influences stereochemical integrity during pyrimidine synthesis. Full article

Antiviral drug resistance in SARS-CoV-2 is increasingly limiting treatment efficacy. Four recent studies have revealed two key resistance mechanisms: (1) Mutations in the main protease (M^pro)—including E166V, E166A, and S144-series variants—disrupt drug binding or active-site conformation, reducing nirmatrelvir efficacy. (2) The proofreading exoribonuclease (ExoN) removes incorporated nucleoside analogues (e.g., bemnifosbuvir, sofosbuvir), conferring resistance. Guided by structural and pharmacological insights, three effective countermeasures have been established: structure-based optimization of M^pro inhibitors, rational design of ExoN-evading nucleoside analogues, and synergistic combination therapies. These advances provide a solid framework for developing next-generation antivirals to combat emerging resistant SARS-CoV-2 variants. Full article

Glucagon-like peptide-1 (GLP-1) analogues are a major class of peptide therapeutics used to treat metabolic diseases. GLP-1-derived peptides are characterized by dynamic conformational ensembles in which folding, intermolecular assembly, and aggregation are strictly coupled processes. This study focused on the effects of sequence modifications, such as helix-promoting residues and backbone constraints on the helix-coil equilibrium, as well as lipidation, which creates competing equilibria among monomeric, oligomeric, and albumin-bound forms. These coupled equilibria simultaneously enhance pharmacokinetic properties and modulate conformational stability. We also explored how environmental conditions such as ionic concentration and temperature affect conformation, and emphasize how manufacturing processes act as external perturbations that could impact structural integrity. Moreover, we focus on the increasingly emerging new multi-agonist peptides, noting that their increased sequence complexity broadens conformational diversity and poses challenges to existing design methods. Despite significant experimental progress, predictive models capable of mapping the intricate interconnections among peptide sequences, lipidation patterns, and aggregation pathways remain critically limited. This highlights the importance of integrating biophysics, computation, and process science. The review points out that designing effective GLP-1 therapeutics rationally depends on managing conformational distributions across complex energy landscapes, not just stabilizing individual structures, in order to offer a new framework for developing the next generation of peptide drugs. Full article

Glycoclusters are important molecular tools for studying carbohydrate–protein interactions. It is advantageous to derive glycoclusters from carbohydrate-based scaffolds. Modulating the chair conformation of the scaffolding monosaccharide between ⁴C₁ and ¹C₄ enables the variation in the spatial organisation of the resulting glycoclusters, allowing the consequences for carbohydrate recognition in biological systems to be studied. Recently, we introduced a xylose derivative capable of adopting two complementary chair conformations, which was conjugated to glycoligands via Suzuki–Miyaura cross-coupling to afford homobivalent glycoclusters. Here, we expand this approach by further exploring the potential of xylose as a conformationally ‘switchable’ carbohydrate scaffold. Two additional features were introduced, (i) alkyne groups to facilitate conjugation reactions through click chemistry, and (ii) orthogonal protection to enable the synthesis of heterobivalent glycoclusters in addition to homobivalent analogues. This strategy enabled the synthesis of a focused library of homo- and heterobilvalent glycoclusters, which were subjected to preliminary biological evaluation. Notably, inversion of the chair conformation of the xyloside scaffold exerted a significant effect on the potency of the respective compounds as inhibitors of mannose-specific bacterial adhesion. Full article

Background: Ferrocene-containing compounds have gained attention in medicinal chemistry due to their unique redox and structural properties. This study investigates ferrocene-based analogues of imatinib and nilotinib to define their binding determinants within the ABL1 kinase domain using an integrated in silico approach, in relation to their previously reported cytotoxic activity. Methods: Ligand geometries were optimized at the B3LYP/def2-TZVP level with D3(BJ) dispersion and SMD solvation. Molecular docking against ABL1 (PDB ID: 2HYY) was performed using Glide SP, validated by re-docking and enrichment screening. Docked poses were refined using MM-GBSA (Prime, VSGB 2.1/OPLS4). The most active compounds (9 and 15a), together with the inactive control 15e, were subjected to three independent 500 ns molecular dynamics simulations (Desmond, OPLS4), followed by trajectory analysis including RMSD, RMSF, radius of gyration, SASA, and polar surface area. Results: Compounds 9 and 15a maintained stable binding within the ATP-binding pocket despite lacking the canonical hinge interaction with Met318, indicating hinge-independent binding. Their binding was mainly driven by interactions with Asp381 (DFG motif) and cation–π contacts with Lys271. In contrast, the compound 15e showed unstable binding, increased conformational flexibility, reduced pocket burial, and loss of key stabilizing interactions. Active compounds also preserved stable P-loop dynamics, with Tyr253 engagement suggesting a role in loop stabilization. Compound 9 exhibited the most constrained and reproducible binding mode among all analogues. Conclusions: Ferrocene-based analogues can sustain stable ABL1 binding via non-classical interaction networks independent of hinge recognition. The clear distinction between active compounds and the inactive analogue 15e supports the robustness of the proposed binding mode and provides a structural basis for their reported cytotoxic activity. These findings support further experimental evaluation of ferrocene-containing scaffolds as potential BCR-ABL1 inhibitors. Full article

Two metallacyclic tetranuclear Fe(III) complexes, [{Fe₂(μ-O)(μ-RCOO)₂(tpon)}₂](BPh₄)₄ [R = Me (1), Ph (2)], where the flexible ditopic ligand tpon (N,N,N′,N′-tetrakis(2-pyridylmethyl)octane-1,8-diamine) links two μ-oxo-bis(μ-carboxylato) triple-bridged dinuclear units, have been prepared. Single-crystal X-ray diffraction establishes that both complexes adopt a 26-membered macrocyclic framework featuring an internal cavity capable of guest inclusion. Notably, incorporation of a monoatomic μ-oxo bridge enforces an outward orientation of the ligand alkyl chains, thereby suppressing the “zipper effect” observed in the previously reported Mn(II) analogue and facilitating the encapsulation of an acetone molecule. UV–vis absorption and diffuse-reflectance spectra confirm that the tetranuclear scaffold remains intact in both the solid state and in solution. These results demonstrate that modulating local coordination directionality via μ-oxo bridging is an effective strategy for controlling the global conformation and host–guest properties of large metallasupramolecular architectures. Full article

The surface of cancer cells is covered in abnormal carbohydrate antigens that facilitate tumor growth, immune evasion and metastasis. Overexpressed and often specific to cancer cells, these tumor-associated carbohydrate antigens (TACAs) offer a valuable handle for targeted immunotherapy and were soon targeted by TACA–protein conjugate vaccines. Despite good initial results, sTn-KLH conjugate Theratope^® failed in clinical trials fifteen years ago for failure to improve life expectancy. This has been attributed to poor immunogenicity, inhomogeneous expression of TACAs within tumors, and vaccine carrier interference. This review covers the two decades of subsequent effort to overcome these limitations and the now large toolbox available to vaccine researchers to improve the outcome of anticancer vaccines: analogues and conformation-locked mimics of TACAs, monomolecular multivalent vaccines, more biologically relevant presentation of TACAs through clusters and glycopeptides, and a new generation of vaccine carriers to reduce carrier interference, immune reaction, or provide simple modular vaccine delivery platforms. Full article

Background: There is currently increasing interest in atypical opioid compounds capable of expanding their clinical applications beyond pain management, including the treatment of psychiatric disorders and substance abuse. In this context, the cyclotetrapeptide c[Trp-Phe-D-Pro-Phe] (CJ-15,208, 1) and its derivatives represent an unusual class of opioid peptides. This compound was found to be a mixed KOR/MOR antagonist in vitro, but it acted as an agonist in vivo. For its diverse analogues, it appeared that receptors’ affinity, selectivity, and agonist/antagonist activity greatly varied upon modifications to backbone geometry and the 3D display of pharmacophores. Methods: We utilized NMR, molecular dynamics, and molecular docking to analyze 3D structures and pharmacodynamic properties of selected representative cyclopeptide analogues of 1. Results: The simulations support that, despite its contradictory functional activity in vitro and in vivo, 1 can bind to the active conformation of receptors in an agonist-like fashion. In general, Trp appeared to be the fundamental pharmacophore in the ligand–receptor complexes. In particular, agonists showed a direct interaction between the indole ring and the carboxylate of the conserved Asp(3:32). Conclusions: These studies support a distinctive pharmacodynamic model for this class of compounds, potentially useful for the design of opioid compounds with novel binding/activity profiles and improved therapeutic effects. Full article

Tubulin is a heterodimeric protein composed of α- and β-subunits, which polymerize to form the cell’s microtubules. The latter are key components in mitotic spindle formation and essential targets in anticancer therapy. Compounds such as paclitaxel, tubulysins, dolastatins and synthetic analogues of these latter compounds, including cemadotin, exert their cytotoxic effects by disrupting microtubule dynamics. Previously, we reported the production and anticancer activity of a library of cemadotin analogues featuring a C-terminal tertiary amide functionalized with a variety of N-substituents, thus resulting in compounds occurring as a mixture of amide rotamers. Here we describe a comprehensive NMR and conformational study that provides new insights into the effect of the conformational equilibrium on the binding mode of the novel cemadotin analogues to the tubulin target. The conformational behavior of the isomer equilibrium of cemadotin’s terminal amide bond was investigated by TOCSY and ROESY NMR experiments, which allowed the identification and quantification of individual rotamer populations. A slow interconversion between the s-cis and s-trans amide rotamers was observed under standard NMR conditions (25 °C), indicating a significant energy barrier and conformational rigidity. Molecular docking and saturation transfer difference (STD) NMR experiments were performed with a representative analogue and tubulin to assess the binding mode. The results revealed that the s-trans rotamer is the predominant conformer in solution and exhibits a more favorable interaction with tubulin compared to the s-cis isomer, thus helping to understand the conformational requirements for an improved tubulin binding and the inhibition of the polymerization process. Full article

Cyclin-dependent kinase 2 (CDK2) plays a central role in cell cycle regulation and represents an important molecular target in anticancer drug development. In this study, a series of novel isatin derivatives substituted with a trifluoromethoxy group at the C6 position were designed and evaluated as potential CDK2 inhibitors using a comprehensive in silico approach. Density functional theory calculations were applied to analyze the electronic properties of the proposed compounds. Molecular docking and molecular dynamics simulations were used to investigate binding modes, conformational stability, and key interactions within the CDK2 active site. Binding free energies were estimated using the Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) method, while QSAR-based (Quantitative Structure–Activity Relationship) ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses were performed to assess drug-likeness and pharmacokinetic profiles. The results indicate that the investigated derivatives form stable complexes with CDK2, supported by persistent hydrogen bonds in the hinge region and favorable hydrophobic interactions. The trifluoromethoxy substituent significantly affects ligand orientation and promotes deeper insertion into the hydrophobic pocket compared with previously studied isatin analogues. ADMET predictions suggest generally favorable absorption and toxicity profiles, with moderate solubility limitations. Overall, these findings support the potential of 6-trifluoromethoxy-isatin derivatives as promising CDK2 inhibitors and provide a basis for further experimental studies. Full article

The increasing crisis of antimicrobial resistance requires innovative therapeutic strategies that can overcome the limitations of conventional antibiotics. Based on our previous finding that AP10 (a derivative of AP29) possesses antimicrobial activity but lacks thermal stability, we rationally redesigned ten new AP10 analogues to enhance functional robustness while maintaining efficacy. Among these, AP10RW is identified as the optimal candidate due to its exceptional broad-spectrum activity against both drug-sensitive and multidrug-resistant (MDR) bacterial pathogens. Structural analysis reveals that AP10RW adopts an environmentally responsive conformation, transitioning from random coil to amphiphilic α-helix in membrane-mimicking environments, while demonstrating remarkable stability under challenges including serum exposure, varying pH, high salt concentrations, and thermal stress. Mechanistic studies indicate that AP10RW exerts its effects through multiple bactericidal mechanisms involving initial high-affinity binding to bacterial characteristic molecules (LTA, LPS and PGN), followed by rapid membrane depolarization, ultrastructural damage and the induction of lethal oxidative stress. Notably, this potent antimicrobial efficacy is coupled with exceptional biosafety, demonstrating little hemolysis and negligible cytotoxicity against mammalian cells. This systematic optimization represents a significant advancement in antimicrobial peptide engineering. We have successfully transformed a thermally unstable peptide into a robust therapeutic candidate and positioned AP10RW as a promising clinical candidate for addressing the growing threat of multidrug-resistant infections. Full article