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One of the most recent focuses in supramolecular chemistry is developing molecules designed to exhibit programmable properties at the molecular level. Rotaxanes, which function as molecular machines with movements controlled by external stimuli, are prime candidates for this purpose. However, the controlled synthesis of rotaxanes, especially amide-benzylic rotaxanes with more than two components, remains an area ripe for exploration. In this study, we aim to elucidate the formation of amide-benzylic [3]rotaxanes using a thread that includes a conventional succinamide station and an innovative triazole-carbonyl station. Including the triazole-carbonyl station introduces new perspectives into the chemistry of rotaxanes, influencing their conformation and dynamics. The synthesis of two-station rotaxanes with varying stoppers demonstrated that the macrocycle consistently occupies the succinamide station, providing greater stability as evidenced by NMR and SC-XRD analyses. The presence of a triazole-carbonyl station facilitated the formation of a second macrocycle exclusively when a secondary amide was employed as the stopper group, presumably due to decreased steric hindrance. Moreover, the second macrocycle directly forms at the triazole-carbonyl station. This investigation reveals that slight modifications in the thread structure can dramatically impact the formation, stability, and interactions between components of rotaxanes.

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Regular intake of fucosylated oligosaccharides has been associated with several benefits for human health, particularly for new-borns. Since these biologically active molecules can be found naturally in human milk, research efforts have been focused on the alternative synthetic routes leading to their production. In particular, utilization of fucosidases to perform stereoselective transglycosylation reactions has been widely investigated. Other reasons that bring these enzymes to the spotlight are their role in viral infections and cancer proliferation. Since their involvement in the pathogenesis of these diseases have been widely described, fucosidases have become a target in newly developed therapies. Finally, activity disorders of biologically important fucosidases can lead to health problems such as fucosidosis. What is common for both mechanisms is the interaction between the enzyme and substrates in and around the active site. Therefore, this review will analyse different substrate structures that have been tested in terms of their interaction with fucosidases active sites, either in synthesis or inhibition reactions. The published results will be compared from this perspective.

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The coordination of one and two aflatoxin B1 (AFB1, a potent carcinogen) molecules with chlorophyll a (chl a) was studied at a theoretical level. Calculations were performed using the M06-2X method in conjunction with the 6-311G(d,p) basis set, in both gas and water phases. The molecular electrostatic potential map shows the chemical activity of various sites of the AFB1 and chl a molecules. The energy difference between molecular orbitals of AFB1 and chl a allowed for the establishment of an intermolecular interaction. A charge transfer from AFB1 to the central cation of chl a was shown. The energies of the optimized structures for chl a show two configurations, unfolded and folded, with a difference of 15.41 kcal/mol. Chl a appeared axially coordinated to the plane (α-down or ß-up) of the porphyrin moiety, either with the oxygen atom of the ketonic group, or with the oxygen atom of the lactone moiety of AFB1. The complexes of maximum stability were chl a 1-α-E-AFB1 and chl a 2-ß-E-AFB1, at -36.4 and -39.2 kcal/mol, respectively. Additionally, with two AFB1 molecules were chl a 1-D-2AFB1 and chl a 2-E-2AFB1, at -60.0 and -64.8 kcal/mol, respectively. Finally, biosorbents containing chlorophyll could improve AFB1 adsorption.

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Repellents are compounds that prevent direct contact between the hosts and the arthropods that are vectors of diseases. Several studies have described the repellent activities of natural compounds obtained from essential oils. In addition, these chemical constituents have been pointed out as alternatives to conventional synthetic repellents due to their interesting residual protection and low toxicity to the environment. However, these compounds have been reported with short shelf life, in part, due to their volatile nature. Nanoencapsulation provides protection, stability, conservation, and controlled release for several compounds. Here, we review the most commonly used polymeric/lipid nanosystems applied in the encapsulation of small organic molecules obtained from essential oils that possess repellent activity, and we also explore the theoretical aspects related to the intermolecular interactions, thermal stability, and controlled release of the nanoencapsulated bioactive compounds.

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The pineal melatonin (N-acetyl-5-methoxytryptamine) is a molecule associated in a way or another with probably all physiological systems, aiming to fulfil its functional integrative roles in central nervous system activity, sleep and wakefulness cycles, energy metabolism and thermoregulation, immune, reproductive, endocrine, cardiovascular, respiratory and excretory systems. Within this context, the present study aimed to assess in silico the formation of complexes between ligand melatonin and other potential receptor proteins by molecular docking analyses. The main steps established in this experimental procedure were: a) search and selection of the 3D structure of the melatonin from DrugBank; b) search and selection of 3D structures of other target receptor proteins using STRING, protein BLAST and database PDB; and c) formation of the complexes between melatonin and receptors selected using AutoDock4.0 server by molecular docking analyses. High reliability score and significant similarity were only identified between type 1B melatonin and alpha-2A adrenergic receptor. Thus, molecular docking assays were carried out using ligand melatonin and crystallographic structures of the alpha-2A adrenergic receptor coupled to an antagonist (ID PDB 6kux) and a partial agonist (ID PDB 6kuy) available in the database PDB. Binding energy values of -6.79 and -6.98 kcal/mol and structural stability by non-covalent intermolecular interactions were predicted during the formation of complexes between melatonin and alpha-2A adrenergic receptor 6kux and 6kuy, respectively. In this way, the findings described in current study may indicate strong interactions between melatonin and adrenoceptors, suggesting its possible partial agonist effect on the activation of the alfa-2A adrenergic receptor.(AU)

A melatonina pineal (N-acetil-5-metoxitriptamina) é uma molécula associada de um modo ou outro com provavelmente todos os sistemas fisiológicos, visando cumprir seus papéis funcionais integradores na atividade do sistema nervoso central, ciclos de sono e vigília, metabolismo energético e termorregulação, sistemas imunológico, reprodutivo, endócrino, cardiovascular, respiratório e excretor. Assim, o presente estudo objetivou avaliar in silico a formação de complexos entre o ligante melatonina e outras proteínas potenciais receptoras por meio de análises de docagem molecular. As principais etapas estabelecidas neste procedimento experimental foram: a) busca e seleção da estrutura 3D da melatonina a partir do banco de dados DrugBank; b) busca e seleção de estruturas 3D de outras proteínas receptoras-alvo utilizando STRING, proteína BLAST e o banco de dados PDB; e c) avaliação da formação dos complexos entre melatonina e receptores selecionados a partir do servidor AutoDock4.0 para análises de docagem molecular. Alto escore de confiabilidade e similaridade significativa foram identificados apenas entre a melatonina do tipo 1B e o receptor alfa-2A adrenérgico. Valores de energia de ligação de -6,79 e -6,98 kcal/mol e estabilidade estrutural pela presença de interações intermoleculares não covalentes foram preditos durante a formação de complexos entre o ligante melatonina e os receptores adrenérgico alfa-2A 6kux e 6kuy, respectivamente. Dessa forma, os achados descritos no presente estudo podem indicar fortes interações entre melatonina e adrenoceptores, sugerindo seu possível efeito agonista parcial na ativação do receptor alfa-2A adrenérgico.(AU)

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The binding between anticancer drugs and double-stranded DNA (dsDNA) is a key issue to understand their mechanism of action, and many chemical methods have been explored on this task. Molecular docking techniques successfully predict the affinity of small molecules into the DNA binding sites. In turn, various DNA-targeted drugs are electroactive; in this regard, their electrochemical behavior may change according to the nature and strength of interaction with DNA. A carbon paste electrode (CPE) modified with calf thymus ds-DNA (CPDE) and computational methods were used to evaluate the drug-DNA intercalation of doxorubicin (DOX), daunorubicin (DAU), idarubicin (IDA), dacarbazine (DAR), mitoxantrone (MIT), and methotrexate (MTX), aiming to evaluate eventual correlations. CPE and CPDE were immersed in pH 7 0.1 mM solutions of each drug with different incubation times. As expected, the CPDE response for all DNA-targeted drugs was higher than that of CPE, evidencing the drug-DNA interaction. A peak current increase of up to 10-fold was observed; the lowest increase was seen for MTX, and the highest increase for MIT. Although this increase in the sensitivity is certainly tied to preconcentration effects of DNA, the data did not agree entirely with docking studies, evidencing the participation of other factors, such as viscosity, interfacial electrostatic interactions, and coefficient of diffusion.

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In recent years, researchers working in biomedical science and technology have investigated alternatives for enhancing the mechanical properties of biomedical materials. In this work, sodium alginate (SA) hydrogel-reinforced nanoparticles (NPs) of hydroxyapatite (HA) were prepared to enhance the mechanical properties of this polymer. Compression tests showed an increase of 354.54% in ultimate compressive strength (UCS), and 154.36% in Young's modulus with the addition of these NPs compared with pure SA. Thermogravimetric analysis (TGA) revealed that the amount of residual water is not negligible and covered a range from 20 to 35 wt%, and the decomposition degree of the alginate depends on the hydroxyapatite content, possibly due to the displacement of sodium ions by the hydroxyapatite and not by calcium chloride. Further, there is an important effect possibly due to the existence of an interaction of hydrogen bonds between the hydroxyl of the alginate and the oxygen atoms of the hydroxyapatite, so signals appear upfield in nuclear magnetic resonance (NMR) data. An increase in the accumulation of HA particles was observed with the use of X-ray microtomography, in which the quantified volume of particles per reconstructed volume corresponded accordingly to the increase in the mechanical properties of the hydrogel.

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The compound 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-9-ol (9-hydroxyeucaliptol) has been prepared and characterized by single-crystal X-ray diffraction analysis, infrared, Raman, and UV-visible spectroscopies. The molecular geometry of the title compound was also investigated theoretically by density functional theory (DFT) calculations to compare with the experimental data. The substance crystallizes in the trigonal crystal system, space group P32 with Z = 9 molecules per unit cell. There are three independent molecules in the crystal asymmetric unit having the same chirality and showing some differences in the orientation of the H-atom of the hydroxyl group. The crystal structure of 9-hydroxyeucaliptol shows that the hydroxyl group presents an anti-conformation with respect to the O-atom of the ether group. The crystal packing of 9-hydroxyeucaliptol is stabilized by intermolecular O-H···O hydrogen bonds involving the hydroxyl groups of different molecules, which play a decisive role in the preferred conformation adopted in solid state. The intermolecular interactions observed in solid state were also studied through the Hirshfeld surface analysis and quantum theory of atoms in molecules (QTAIM) approaches. Energy framework calculations have also been carried out to analyze and visualize the topology of the supramolecular assembly, and the results indicate a significant contribution from electrostatic energy over the dispersion.

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Acrocomia totai Mart (Arecaceae) is a palm tree native to South America, widely studied for biodiesel production. The aim of this work was to perform the first phytochemical study of A. totai leaves, as well as to do biological assays against human cancer cell lines. A new triterpene of the hopane class named totaiol (1), three known triterpenes (2-4), and two phytosteroids (5-6) were identified. The new natural product was characterized using 1 D and 2 D NMR, single crystal X-ray diffraction analises, and high resolution mass spectrometry. The intercontacts in the crystal packing were also analised. Complete stereochemical characterization of compound 1 revealed an unusual positioning pattern for methyl and isopropenyl groups in the polycyclic skeleton. Compounds 1-5 were evaluated for the first time in antiproliferative assays against Ca Ski, MCF-7 and MCF-10 cells. The new natural product was active against Ca Ski cells with IC50 ≤ 6.25 µg mL-1.

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Several studies with substitution-inert polynuclear platinum(II) complexes (SI-PPC) have been carried out in recent years due to the form of DNA binding presented by these compounds. This form of bonding is achieved by molecular recognition through the formation of non-covalent structures, commonly called phosphate clamps and forks, which generate small extensions of the major and minor grooves. In this work, we use molecular dynamics simulations (MD) to study the formation of these cyclical structures between six different SI-PPCs and a double DNA dodecamer, here called 24_bp_DNA. The results showed the influence of the complex expressed on the number of phosphate clamps and forks formed. Based on the conformational characterization of the DNA fragment, we show that the studied SI-PPCs interact preferentially in the minor groove, causing groove spanning, except for two of them, Monoplatin and AH44. The phosphates of C-G pairs are the main sites for such non-covalent interactions. The Gibbs interaction energy of solvated species points out to AH78P, AH78H, and TriplatinNC as the most probable ones when coupled with DNA. As far as we know, this work is the very first one related to SI-PPCs which brings MD simulations and a complete analysis of the non-covalent interactions with a double DNA dodecamer.

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The physical adsorption of cisplatin (CP) on graphene oxide (GO) and reduced graphene oxide (rGO) is investigated at the DFT level of theory by exploiting suitable molecular prototypes representing the most probable adsorbing regions of GO and rGO nano-structures. The results show that the CP binding energy is enhanced with respect to that for the interaction with pristine graphene. This is due to the preferential adsorption of the drug in correspondence of the epoxy and hydroxy groups located on GO basal plane: an energy decomposition analysis of the corresponding binding energy reveals that the most attractive contribution comes from the electrostatic attraction between the -NH 3 ends of CP and the oxygen groups on (r)GO, which can be associated with hydrogen bonding effects. Moreover, it is found that the reactivity of the physically adsorbed CP is practically unaltered being the free energy variation of the first hydrolysis reaction almost matching that of its free (unadsorbed drug) counterpart. The reported results suggest that the CP physical adsorption on GO and rGO carriers is overall feasible being an exergonic process in aqueous solution. The CP adsorption could facilitate its solubility and transport in water solutions, exploiting the high hydrophilicity of the peripheral carboxylic groups located on the edge of the GO and rGO nano-structures. Moreover, the the higher affinity of CP with respect to the oxidized sites suggests a possible dependence of drug loading and release on pH conditions, which would highly facilitate its specific delivery.

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The structure of bioactive compounds inside their biological target is mainly dictated by the intermolecular interactions present in the binding side, whereas intramolecular interactions are responsible for the structure of an isolated molecule. Accordingly, this work reports the relative significance of these interactions for the bioactive conformation of the N-protonated epinephrine. The crystallized structure of epinephrine has a gauche orientation of the O-C-C-N torsion angle. Conformational analysis in the gas phase and implicit water was performed to investigate the main intramolecular forces favoring this conformational preference, which was primarily attributed to the electrostatic interaction between hydroxyl and ammonium groups. However, when the conformers were docked into the active site, intramolecular interactions were surpassed by intermolecular hydrogen bonds with neighboring amino acid residues. Nonetheless, structural modifications aiming at strengthening intramolecular interactions could be used to modulate a bioactive conformation, thereby assisting in the structure-based design of new chemical entities.

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A response is given to comments by Bürgi & Macchi [IUCrJ (2018), 5, 654-657] about Belo et al. [IUCrJ (2018), 5, 6-12.].

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Enantiomeric amino acids have specific physiological functions in complex biological systems. Systematic studies focusing on the solid-state properties of d-amino acids are, however, still limited. To shed light on this field, structural and spectroscopic studies of d-alanine using neutron powder diffraction, polarized Raman scattering and ab initio calculations of harmonic vibrational frequencies were carried out. Clear changes in the number of vibrational modes are observed as a function of temperature, which can be directly connected to variations of the N-D bond lengths. These results reveal dissimilarities in the structural properties of d-alanine compared with l-alanine.

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Isothermal titration calorimetry (ITC) is a commonly used biophysical technique that enables the quantitative characterization of intermolecular interactions in solution. Based on enthalpy changes (ΔH) upon titration of the binding partner (e.g., a small-molecule ligand such as c-di-GMP) to the molecule of interest (e.g., a receptor protein), the resulting binding isotherms provide information on the equilibrium association/dissociation constants (K a, K d) and stoichiometry of binding (n), as well as on changes in the Gibbs free energy (ΔG) and entropy (ΔS) along the interaction. Here we present ITC experiments used for the characterization of c-di-GMP binding proteins and discuss advantages and potential caveats in the interpretation of results.

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