Search Results (210)

Hydrogen-bond organization plays a central role in determining the structure and properties of water from molecular to macroscopic scales. In this study, we propose a geometry-based descriptor for small hydrogen-bonded water clusters, (H₂O)_n, with n = 2–6. The central element of the proposed geometric framework is the dimensionless geometric index, S_n = d/l, where d is the center-to-molecule distance in a cluster configuration and l is the nearest-neighbor O···O distance associated with hydrogen-bonded water molecules. The geometric descriptor is not intended to replace quantum-chemical calculations or to provide a direct measurement of hydrogen-bond energy, lifetime, or number. Instead, it provides a compact geometric framework for describing the structural organization of small hydrogen-bonded water clusters. The obtained geometric trend is compared with selected Nuclear Magnetic Resonance (NMR), Møller–Plesset perturbation theory (MP2), and radial distribution function data as complementary qualitative and semi-quantitative references. The proposed geometric index S_n = ${\displaystyle \frac{d}{l}}$ was further compared with MP2 quantum-chemical O···O distances for (H₂O)_n clusters, n = 2–6, using the oxygen atoms as structural nodes of the hydrogen-bonded motifs. This comparison showed that the exponential increase in S_n is consistent with the characteristic O···O donor–acceptor length scale of approximately 2.8 Å, linking the geometric framework with calculated molecular geometries. Over the limited interval n = 2–6, the geometric index Sn increases monotonically and nonlinearly with cluster size. The quantum-chemical reference data previously reported in our study, comprising GIAO-DFT-calculated ¹H chemical shifts obtained for MP2-optimized water-cluster geometries, show a rapid nonlinear increase from the dimer to the pentamer, followed by the onset of saturation in the pentamer–hexamer range. The semi-empirical stabilization parameter evaluated in the present study indicates increasing relative stabilization, with a reduced incremental change around n ≈ 4–5. The qualitative consistency of these size-dependent trends supports the use of Sn as a compact geometric descriptor of hydrogen-bond organization in small water clusters, without interpreting it as a direct quantitative measure or mechanistic framework of hydrogen-bond cooperativity. Importantly, liquid water is not treated as a system of closed cyclic clusters; cyclic motifs are used only as frameworked geometric reference configurations for small hydrogen-bonded aggregates. The geometric trend is qualitatively compared with selected quantum-chemical, spectroscopic, and radial distribution function data and should be regarded as an empirical geometric approximation over the limited interval n = 2–6. These findings indicate that geometric, spectroscopic, and quantum-chemical descriptors reflect related, but not identical, aspects of hydrogen-bond organization. The proposed approach links cluster geometry, O···O intermolecular distances, and hydrogen-bond connectivity in a simplified geometric description. Full article

Age-related skeletal muscle atrophy (sarcopenia) poses a major public health challenge, emphasizing the need for safe and effective interventions. Our previous studies demonstrated that C-C chemokine receptor type 5 (CCR5) is a key therapeutic target for skeletal muscle atrophy, as its activation by C-C motif chemokine ligand 11 (CCL11) promotes the dissociation and degradation of the structural protein α-actin, ultimately contributing to muscle loss. To identify potential CCR5 inhibitors, a database of 7860 natural alkaloids was constructed for pharmacophore-based virtual screening using the CCR5–Maraviroc crystal structure. Screening yielded 789 candidates, and subsequent batch molecular docking analysis identified Isoliensinine (ISO), a lotus seed alkaloid, as a potential CCR5 inhibitor with low binding energy (−10 kcal/mol) and stable hydrogen bonding interactions with Glu283 and Tyr251. Molecular dynamics simulations further confirmed the structural stability of the ISO–CCR5 complex. Molecular dynamics simulations further confirmed the structural stability of the ISO-CCR5 complex. In vitro, ISO dose-dependently inhibited CCL11-induced CCR5 activity (IC₅₀ = 1.314 μM) with low cytotoxicity in C2C12 myotubes, and markedly alleviated CCL11-induced myotube atrophy by suppressing CCR5 activation and the upregulation of the muscle atrophy–related markers MAFbx and MuRF1. These findings provide preliminary evidence for ISO as a potential CCR5-targeting candidate for further investigation in sarcopenia. Full article

Full-length ACTH molecule and ACTH-related hexapeptide H-PKKRRP-OH are demonstrated by the patch-clamp method to decrease the Na_V1.8 channel activation gating system effective charge in the nociceptive neuron membrane, while ACTH-related tetrapeptide Ac-KKRR-NH₂ has no effect. ACTH(1–24), a fully functional ACTH mimetic, and H-PKKRRP-OH show analgesic effects in the formalin test in vivo. All peptides contain the cationic KKRR motif, but only H-PKKRRP-OH and ACTH(1–24) relieve acute pain, targeting the Na_V1.8 channel as a receptor. This seemingly controversial result is explained by application of conformational analysis and blind docking. Though conformational analysis indicates that both H-PKKRRP-OH and Ac-KKRR-NH₂ contain the cationic functional groups at the earlier suggested characteristic distance of 9–12 Å, Ac-KKRR-NH₂ does not interact with the S4_I voltage sensor of the Na_V1.8 channel activation gating system. The docking demonstrates that an extensive network of ligand–receptor ionic and hydrogen bonds involving D151, E157, R218, and R221 VSD_I residues, essential for the analgesic tripeptide Ac-KKK-NH₂ binding, is formed upon the H-PKKRRP-OH binding. Particularly important are the ionic bonds between the H-PKKRRP-OH C-terminal carboxylate anion and the S4_I R218 and R221 guanidinium groups. The described mechanism of Na_V1.8 channel modulation is fundamentally different from the effect of channel blockers. Full article

Cinnamoyl coenzyme A reductase (CCR) is the first rate-limiting enzyme in the monolignol-specific pathway and plays a pivotal role in lignin biosynthesis. However, CCR genes in Pinus yunnanensis remain uncharacterized, and their undefined substrate specificity further impedes mechanistic insights into lignin regulation while restricting strategies for wood property optimization. Using conserved domain and homology analysis, with a focus on the characteristic NAD(P)-binding motif (KNWYCYGK), we identified 12 CCR family members from the transcriptome data of P. yunnanensis. Phylogenetic analysis clustered the PyCCRs into two distinct clades: PyCCR1~6 fall into the CCR clade, while the remaining members form a CCR-like clade. In this study, twelve ORF regions of the P. yunnanensis CCR genes were cloned, and nine purified recombinant PyCCR proteins were obtained through prokaryotic expression. In vitro enzymatic assays demonstrated that PyCCR1, PyCCR2, PyCCR5, and PyCCR6 catalyzed the conversion of p-coumaroyl-CoA, feruloyl-CoA, and sinapoyl-CoA to p-coumaraldehyde, coniferaldehyde, and sinapaldehyde, respectively. Molecular docking of PyCCR1 to 6 with three substrates identified substrate-binding pocket domains. Within these domains, hydrogen bonds formed between ligands and residues in the R(X)5K motif of PyCCR1 to 6, whereas PyCCRL7 to 12 lacked the complete motif. RT-qPCR analysis showed tissue-specific expression patterns of the 12 genes across buds, stems, leaves, roots, and fruits. Collectively, these findings suggest that the presence of a complete R(X)5K motif may play a crucial role in maintaining the catalytic activity of PyCCRs. Our present study established a mechanistic foundation for elucidating lignin biosynthesis regulation in P. yunnanensis and offer genetic resources for improvement programs. Full article

A comparative study was carried out using density functional theory of the adsorption of phenol and p-chlorophenol on two molecular models of biopolymers in aqueous medium: a chitosan dimer and cellobiose. Twelve adsorbent–adsorbate complexes with three initial orientations per system were optimized, and their structural, electronic, and non-covalent properties were analyzed using boundary orbitals, molecular electrostatic potential, NCI/RDG, and QTAIM. In all four systems, the most stable geometry corresponded to the anchoring of the contaminant hydroxyl group to an adsorbent hydroxyl group, identifying O–H···O as the guiding motif of molecular recognition. However, conformational selectivity was strongly dependent on the adsorbent and the aromatic substituent. For phenol, the alternative orientations were 2.7 and 21.2 kcal mol⁻¹ in chitosan and 6.6 and 48.9 kcal mol⁻¹ in cellobiose. For p-chlorophenol, chitosan showed a much more severe discrimination, with penalties of 43.6 and 46.44 kcal mol⁻¹. In contrast, in cellobiose, the alternative orientations remained close to the minimum, with differences of 5.1 and 3.5 kcal mol⁻¹. The effect of Cl was also reflected in the electron topology: PC increased from 3.2 × 10⁻² to 6.34 × 10⁻² a.u. in chitosan and from 3.2 × 10⁻² to 4.2 × 10⁻² a.u. in cellobiose, while |V|/G went from 3.6 to 7.5 in chitosan and from 3.00 to 3.1 in cellobiose. Overall, the results show that p-chlorophenol interacts more intensely and selectively with chitosan, whereas cellobiose favors a more flexible, less topologically differentiated adsorption. These results clarify how a para-chloro substituent reorganizes hydrogen-bond-driven adsorption on two biopolymer microenvironments with different functional heterogeneity. Full article

In this work, three 3-carboxamidecoumarin derivatives (3b, 3c, and 4) were synthesized and characterized by NMR, IR, and single-crystal X-ray. All compounds maintain an essentially planar coumarin scaffold stabilized by an intramolecular N–H⋯O hydrogen bond (S(6) motif), though compound 4 exhibits a more complex bifurcated S₃²(11)[S(6)S(6)S(5)] network that enhances its conformational rigidity. The crystal packing analysis reveals that while all derivatives form one-dimensional (1D) supramolecular tapes through C–H⋯O interactions, their 3D architectures differ significantly: 3b and 3c rely on a diverse combination of π⋯π stacking and lone pair⋯π contacts, whereas 4 is governed by highly directional stacking between the pyran and pyridine rings. Hirshfeld surface analysis and CE-B3LYP energy framework calculations quantified the balance between intermolecular forces, showing that 3b is dispersion-dominated (H⋯H, 43.5%), while 3c achieves a balanced electrostatic–dispersion regime due to the nitro group, which increases O⋯H/H⋯O contacts to 37.1% and yields the highest stabilization energy (−69.1 kJ/mol). These results demonstrate that the electronic nature of the substituents at the 3- and 6-positions drastically modulates the hierarchy of non-covalent interactions, providing key insights for the crystal engineering of coumarin-based supramolecular systems. Full article

Intermolecular interactions play an important role in the formation and stability of co-crystals. In this study, the interaction behaviour of theophylline in co-crystal structures was systematically analysed using data from the Cambridge Structural Database. A total of fifty-three theophylline co-crystal structures were investigated and classified according to their intermolecular interaction motifs. A structured interaction scheme was developed to describe the accessible interaction sites of theophylline, including classical and non-classical hydrogen bonds, as well as halogen bonds and π∙∙∙π interactions. The study revealed theophylline’s high versatility in forming intermolecular interactions, resulting in twenty interaction patterns. Three dominant motifs were identified as occurring most frequently. The results indicate that steric effects influence the accessibility of specific interaction sites, particularly limiting interactions at the carbonyl group located between the two methyl groups. Hirshfeld surface analysis revealed that O∙∙∙H and H∙∙∙H interactions contribute most significantly to the intermolecular interactions in the analysed structures. Full article

Background: Neglected diseases caused by protozoan parasites remain a major public health burden, particularly in low- and middle-income countries. Among the chemical motifs explored in antiparasitic drug discovery, guanidine-containing compounds have attracted considerable attention due to their strong cationic character, high capacity for hydrogen bonding, and versatility in interacting with biological targets. Methodology: This review summarizes advances reported in the last decade regarding guanidine derivatives with activity against pathogens associated with Chagas disease, human African trypanosomiasis, Leishmaniasis, tuberculosis, toxoplasmosis, dengue and schistosomiasis. Results: Evidence gathered from synthetic, natural, and drug-repurposing studies indicates that the guanidine, guanidine-containing and guanidine-related compounds contribute to modulating biological activity by changing electrostatic interactions, hydrogen-bonding networks, and physicochemical properties, with enzymes, nucleic acids, and membrane-associated targets essential for parasite survival. Across the analyzed studies, several emerging structure–activity relationship trends were identified, including the contribution of polycationic or dicationic architectures, the influence of halogenated or lipophilic substituents, and the dependence of biological activity on the complete molecular framework, including heterocyclic systems, macrocycles, peptide conjugates, hybrid scaffolds, and repurposed drugs. In addition to direct antiparasitic effects, certain guanidine-containing and guanidine-related compounds demonstrate immunomodulatory or host-protective properties, expanding the therapeutic relevance of this class. Despite promising in vitro results, protonation trapping, efflux pump susceptibility, and pharmacokinetic limitations such as poor oral absorption, high polarity, plasma protein binding and limited membrane permeability remain significant challenges for clinical translation. Nonetheless, the integration of medicinal chemistry, computational modeling, and biological screening continues to accelerate the identification of optimized scaffolds. Conclusions: Overall, guanidine-based compounds constitute a promising scaffold for the development of new therapeutic strategies targeting neglected parasitic diseases, and further structural optimization may enable the emergence of candidates with improved efficacy, selectivity, and drug-like properties. Full article

4-Methyl- (1) and 4-ethyl-8-hydroxyquinoline (2) crystallize from a mixture of diethyl ether and chloroform in the triclinic space group P$\overline{1}$. X-ray analysis reveals that both compounds form discrete molecular dimers stabilized by intermolecular O-H∙∙∙N and C-H∙∙∙O hydrogen bonds, resulting in $R_2^2\left(5\right)$ cyclic synthons. This pattern of hydrogen bonds is further stabilized by intramolecular O-H∙∙∙N bonds so that the quinoline nitrogen atom acts as a bifurcated binding site. The dimers exhibit a planar geometry and arrange into layer-like structures held together by π∙∙∙π stacking and van der Waals forces. While the fundamental bonding motifs are similar, the increased steric demand of the ethyl group in compound 2 induces a shift in the crystallographic orientation of the layers and alters the degree of π-overlap compared to the methyl-substituted analogue 1. Full article

Protein recognition underpins advances in drug discovery, immunoassays, clinical diagnostics and biosensing. As a biomimetic alternative to natural receptors, molecularly imprinted polymers (MIPs) have been developed to emulate antibody–antigen complementarity by generating binding cavities that mirror the size, shape and functionality of target macromolecules through template-directed polymerization and subsequent template removal. However, protein imprinting has historically been hampered by low imprinting efficiency and limited selectivity, rendering conventional protein-imprinted polymers (PIPs) inadequate for many contemporary biomedical applications. Functional ionic liquids (ILs)—a class of designer solvents and materials distinguished by tunable structures, exceptional physicochemical properties and favorable biocompatibility—have emerged as versatile additives to address the principal limitations of traditional PIPs, including poor selectivity, sluggish mass transfer and destabilization of protein conformation. Here, we provide a systematic review of the multifaceted roles that ILs play within protein-imprinting systems, delineating their employment as template-anchoring motifs, functional monomers, cross-linkers, porogens and structural stabilizers, and evaluating the consequent effects on polymer architecture and recognition performance. We further probe the multiplicity of non-covalent interactions between ILs and template proteins—highlighting the synergistic modulation afforded by electrostatic forces, hydrogen bonding, hydrophobic interactions and π-π stacking—and consider how such interplay can be harnessed to fine-tune binding-site fidelity. Consolidating recent progress, we summarize IL-enabled PIP applications in protein-specific recognition, biosensor development and analysis of complex real-world samples, and we critically examine the prevailing technical challenges and prospects for translation. The evidence indicates that ILs, by furnishing abundant interaction sites, accelerating mass transport and stabilizing native protein conformations, can markedly enhance PIP adsorption capacity, target specificity and recyclability, positioning them as a cornerstone for next-generation protein separation and enrichment materials and paving the way toward industrial deployment of protein-imprinting technologies. Full article

Ten compounds have been prepared among them six different dioxido(pyridine-2,6-dicarboxylato)vanadate(V) compounds with piperazinium (H₂pip²⁺) (1·6H₂O), methylpiperazinium (H₂mepip²⁺) (2·5H₂O), ethylpiperazinium (H₂etpip²⁺) (3·3H₂O), isopropylpiperazinium (H₂isopip²⁺) (4·H₂O), phenylpiperazinium (Hphepip⁺) (5∙H₂O) and thiomorpholinium 1-oxide (HtmorO⁺) (6·2,6-H₂pydc·2H₂O) cations as counterions as well as methylpiperazinium (H₂mepip²⁺) salt of a mixed valence vanadium [VO(2,6-pydc)-(μ-O)-VO(H₂O)(2,6-pydc)]⁻ complex (7), thiomorpholin-4-ium vanadate (Htmor)VO₃ (8), hexa(thiomorpholin-4-ium) decavanadate hexahydrate (Htmor)₆[V₁₀O₂₈]·6H₂O (9·6H₂O) and organic salt cocrystal thiomorpholin-4-ium 6-carboxypicolinate pyridine-2,6-dicarboxylic acid (Htmor)⁺(2,6-Hpydc)⁻∙(2,6-H₂pydc)·2H₂O (10·2H₂O) via different pathways starting either from pyridine-2,6-dicarboxylic acid or its esters, and were structurally characterized by single-crystal X-ray diffraction. Extended hydrogen bonding interactions are present due to the presence of organic cations as well as due to the diverse roles of water molecules in the hydrogen bonding network. Centrosymmetric hydrogen bonding was found to be an important motif, and diverse supramolecular patterns were also observed due to a wide variety of C–H···O and π···π interactions stabilizing the crystal lattices. Full article

Background/Objectives: Protein kinases play a crucial role in cancer initiation, progression, and therapeutic resistance by regulating signalling pathways involved in tumour growth and survival. Consequently, they represent major targets in anticancer drug discovery. Among heterocyclic scaffolds explored in kinase inhibitor design, benzimidazole has emerged as a privileged structure due to its strong hydrogen-bonding capability and structural resemblance to purine moieties. Triazole motifs are also widely incorporated into bioactive molecules because of their metabolic stability, favourable electronic properties, and ability to establish key interactions within kinase active sites. This review aims to summarise and critically discuss benzimidazole- and triazole-based kinase inhibitors, both as individual scaffolds and as hybrid systems, with emphasis on their kinase targets and multitarget potential. Methods: The relevant literature was surveyed from major scientific databases focusing on studies describing the synthesis, biological evaluation, and molecular modelling of benzimidazole- and triazole-containing kinase inhibitors. Results: Numerous studies demonstrate that both benzimidazole and triazole scaffolds exhibit significant kinase inhibitory activity against oncogenic targets, including EGFR, cyclin-dependent kinases (CDKs), and components of the PI3K/Akt/mTOR signalling pathway. Hybrid molecules combining these pharmacophores frequently enhance binding interactions and facilitate the development of multitarget kinase inhibitors. Structure–activity relationship trends indicate that pharmacophore accessibility, substitution patterns, and linker architecture influence inhibitory potency and selectivity. Conclusions: Overall, benzimidazole- and triazole-based scaffolds represent promising platforms for developing next-generation multitarget anticancer agents and provide valuable insights for the rational design of improved kinase inhibitors. Full article

Water exhibits unique interfacial properties that arise from the collective organization of its hydrogen-bond network. Establishing clear links between molecular-scale interactions and macroscopic observables remains a central challenge in understanding the behavior of liquid water. In this work, we combine experimental measurements of the contact angle of sessile water drops with quantum-chemical modeling of small water clusters (H₂O)_n (n = 2–6) to explore multiscale effects of hydrogen-bond cooperativity. The cluster calculations reveal a nonlinear, saturating evolution of hydrogen-bond geometries with increasing cluster size, reflecting the onset of cooperative many-body effects. Experimentally, the evolution of the apparent contact angle during evaporation is quantified using both conventional geometry and a non-invasive geometrical-optical method based on analysis of the dark refractive ring, which provides independent validation against conventional goniometric measurements. The evaporation dynamics are further interpreted within the diffusion-limited framework of the Popov model, indicating that the temporal evolution of the apparent contact angle is primarily consistent with geometry-controlled mass loss under diffusion-limited conditions, rather than requiring variations in intrinsic surface energy. By combining macroscopic contact-angle measurements with molecular-level cluster analysis, this study offers a qualitative multiscale perspective in which minimal cooperative hydrogen-bond motifs provide molecular context for interpreting interfacial behavior, without implying direct quantitative prediction of macroscopic interfacial observables. Full article

Cyclotides are exceptionally stable plant peptides whose biological activity is widely attributed to interactions with lipid membranes, yet the molecular mechanisms underlying these interactions remain incompletely resolved. Here, we employ microsecond-scale (1 μs) all-atom molecular dynamics simulations to investigate the membrane association of the cyclotide kalata B1 with phospholipid bilayers of distinct headgroup composition, including POPC, POPE, and POPG. This extended timescale enables full bilayer equilibration and allows observation of slower peptide-induced membrane responses that are not accessible in shorter simulations. Across all systems, kalata B1 rapidly adsorbs to the membrane surface and remains predominantly surface-associated throughout the simulations, while the cyclic cystine knot motif remains structurally intact, confirming the exceptional robustness of the cyclotide fold during membrane engagement. Lipid-dependent differences arise primarily from variations in peptide orientation, conformational flexibility, and interfacial dynamics rather than deep bilayer insertion or pore formation. Zwitterionic POPC membranes favor compact, upright peptide configurations, whereas POPE and POPG bilayers promote enhanced lateral spreading and dynamic reorganization driven by hydrogen bonding and electrostatic interactions, respectively. Leaflet-resolved analyses of lipid contacts, membrane thickness, and area per lipid reveal localized, asymmetric perturbations confined to the peptide-exposed leaflet, with no evidence of sustained bilayer thinning or global destabilization. Together, these results support an interfacial, headgroup-dependent mechanism of cyclotide membrane activity and reconcile previous experimental observations. This work provides molecular-level insight into lipid selectivity and early-stage cyclotide–membrane interactions that may inform future design of cyclotide-based bioactive agents. Full article

Chiral and racemic forms of a pyridyl ligand (R-L and rac-L, respectively), containing urea groups at their core and synthesised by the condensation of 3-aminopyridine and α-methylbenzylisocyante, were incorporated into silver complexes. The resulting species depend on the enantiopurity of the ligand alongside an influence from the counter-anion. The enantiopure ligand generated isomorphous, one-dimensional polymeric compounds [Ag(R-L)X] (where X = NO₃, CF₃SO₃) or [Ag(R-L)]X (where X = BF₄, PF₆). The polymeric chains, connected by N and O coordination of the ligands, have outwards facing urea groups that form hydrogen bonds to the counter-anions, which play little role in determining the overall structure. Despite all syntheses containing an excess of Ag(I) salt, the racemic ligand formed only discrete complexes of [Ag(rac-L)₂]⁺ in the presence of each of the above anions. Three of these complexes contain ligands of the same chirality (i.e., complexes with R,R and S,S ligand pairs within the centrosymmetric structures) with only the PF₆-containing compound being different. The anions play a role in dictating the structure of hydrogen-bonded chains, although PF₆⁻ is unique with urea···urea interactions present between complexes. Overall, this system highlights the nuances associated with predicting the structure, and even speciation, of related chiral/achiral systems in addition to influences of counter-anions on structural motifs. Full article