An investigation of the predominant structure of antibiotic azithromycin in chloroform solution through NMR and thermodynamic analysis.

Azithromycin (AZM) is a well-known macrolide-type antibiotic that has been used in the treatment of infections and inflammations. Knowledge of the predominant molecular structure in solution is a prerequisite for an understanding of the interactions of the drug in biological media. Experimental structural determination can be carried out for samples in solid-state (X-ray diffraction technique) and gas phase (electron diffraction experiment). In solution, spectroscopic methods can be used to extract valuable information which combined with quantum chemical calculations can lead to the determination of the preferred molecular structures to be observed when a given solute is dissolved in each solvent. That is precisely the aim of this work. We used experimental NMR chemical shift data (in CDCl3) as a reference for comparison with Density Functional Theory (DFT) NMR calculations, with geometry optimized having as guess input two crystallographic structures available in the literature with the configuration of all chiral carbon atoms inverted, named here A and B. The Polarizable Continuum Model (PCM) was used to describe the solvent effects (chloroform) including five explicit CHCl3 solvent molecules, which we believe can account for short and long-range solute-solvent interactions. Analysis of calculated thermodynamic, NMR chemical shift, MAE (Mean Absolute Error), and spin-spin coupling constant values revealed that both supposable C3R-C5S (named M2-A) and C3S-C5R (named M2-B) structures are equally probable to exist in chloroform solution. In addition, we found that the heavy atoms' conformation is reasonably similar in the solid-state and chloroform solution; however, regarding the OH groups, the spatial orientations are rather different with intramolecular OH⋯N and OH⋯O hydrogen bonds present in solution and with some of them being absent in the X-ray structure probably due to crystal packing effects.

Chemically Modified Carbon Nanohorns as Nanovectors of the Cisplatin Drug: A Molecular Dynamics Study.

Carbon nanohorns (CNH) have been considered potential anticancer drug carriers, such as the cisplatin drug (cddp), due to their low toxicity, high purity, drug-loading capacity, and biodegradation routes. However, when it comes to nanomedicine applications, chemical functionalization is an essential step in order to overcome undesirable properties of these nanomaterials, such as the high hydrophobicity, low reactivity, and low dispersibility in polar solvents. In this context, the present study involved the modeling of new CNH topologies based on chemical oxidation and reduction mechanisms and the investigation of the influence of these modified structures on the dynamics and stability of inclusion complexes with cddp. The results indicated that these functionalization strategies lead to the opening of nanowindows on the CNH surfaces, which would constitute the main route for drug release, as reported by experimentalists. Also, our results showed that the insertion of polar functional groups on the oxidized CNH (CNHox-N) contributed to an improvement of the cddp@CNHox-N biocompatibility due to the greater number of hydrogen bonds formed with the solvent. Despite the favorable formation of all complexes, the binding free energies pointed out that the oxidation process made the cddp@CNHox-N complexes slightly less stable than the ones with pristine and reduced CNH. Besides, the results suggest the possibility to tune the complex stability by controlling the oxidation degree, which could be explored by the experimentalists in order to design controlled drug delivery systems based on CNH nanocarriers.

Conformational Analysis of 5,4'-Dihydroxy-7,5',3'-trimethoxyisoflavone in Solution Using 1H NMR: A Density Functional Theory Approach.

Among 20 compounds isolated from the extracts of Ouratea ferruginea the 5,4'-dihydroxy-7,5',3'-trimethoxyisoflavone (9) showed the best inhibitory effect on glutathione S-transferase (GST) and so deserves our attention. In this work we investigated the preferred molecular structure of 9 in chloroform solution using the density functional theory (DFT) and molecular dynamics simulation. Comparison between experimental 1H NMR data in CDCl3 solution and calculated chemical shifts enabled us to precisely determine the conformation adopted by 9 in solution, which can be used in further theoretical studies involving interaction with biological targets. Moreover, the experimental NMR data were used as reference to assess the ability of DFT based methods to predict 1H NMR spectrum in solution for organic compounds. Among various DFT functionals the hybrid B3LYP was the most adequate for the calculation of chemical shifts in what CHn protons are concerned. Regarding the OH hydrogen, inclusion of explicit CHCl3 solvent molecules adequately placed around the solute led to good agreement with the experimental chemical shifts (in CDCl3). It is a well-known fact that theoretical prediction of chemical shifts for OH hydrogens poses as a challenge and also revealed that the way the solvent effects are included in the DFT calculations is crucial for the right prediction of the whole 1H NMR spectrum. It was found in this work that a supermolecule solute-solvent calculation with a minimum of four CHCl3 molecules is enough to correctly reproduce the 1H NMR experimental profile observed in solution, revealing that the calculated solvated structure used to reproduce the NMR chemical shifts is not unique.

Water Solvent Effect on Theoretical Evaluation of 1H NMR Chemical Shifts: o-Methyl-Inositol Isomer.

In this paper, density functional theory calculations of nuclear magnetic resonance (NMR) chemical shifts for l-quebrachitol isomer, previously studied in our group, are reported with the aim of investigating in more detail the water solvent effect on the prediction of 1H NMR spectra. In order to include explicit water molecules, 20 water-l-quebrachitol configurations obtained from Monte Carlo simulation were selected to perform geometry optimizations using the effective fragment potential method encompassing 60 water molecules around the solute. The solvated solute optimized geometries were then used in B3LYP/6-311+G(2d,p) NMR calculations with PCM-water. The inclusion of explicit solvent in the B3LYP NMR calculations resulted in large changes in the 1H NMR profiles. We found a remarkable improvement in the agreement with experimental NMR profiles when the explicit hydrated l-quebrachitol structure is used in B3LYP 1H NMR calculations, yielding a mean absolute error (MAE) of only 0.07 ppm, much lower than reported previously for the gas phase optimized structure (MAE = 0.11 ppm). In addition, a very improved match between theoretical and experimental 1H NMR spectrum measured in D2O was achieved with the new hydrated optimized l-quebrachitol structure, showing that a fine-tuning of the theoretical NMR spectra can be accomplished once solvent effects are properly considered.

The semiquinone at the Qi site of the bc1 complex explored using HYSCORE spectroscopy and specific isotopic labeling of ubiquinone in Rhodobacter sphaeroides via (13)C methionine and construction of a methionine auxotroph.

Specific isotopic labeling at the residue or substituent level extends the scope of different spectroscopic approaches to the atomistic level. Here we describe (13)C isotopic labeling of the methyl and methoxy ring substituents of ubiquinone, achieved through construction of a methionine auxotroph in Rhodobacter sphaeroides strain BC17 supplemented with l-methionine with the side chain methyl group (13)C-labeled. Two-dimensional electron spin echo envelope modulation (HYSCORE) was applied to study the (13)C methyl and methoxy hyperfine couplings in the semiquinone generated in situ at the Qi site of the bc1 complex in its membrane environment. The data were used to characterize the distribution of unpaired spin density and the conformations of the methoxy substituents based on density functional theory calculations of (13)C hyperfine tensors in the semiquinone of the geometry-optimized X-ray structure of the bc1 complex (Protein Data Bank entry 1PP9 ) with the highest available resolution. Comparison with other proteins indicates individual orientations of the methoxy groups in each particular case are always different from the methoxy conformations in the anion radical prepared in a frozen alcohol solution. The protocol used in the generation of the methionine auxotroph is more generally applicable and, because it introduces a gene deletion using a suicide plasmid, can be applied repeatedly.

On the use OF 1H-NMR chemical shifts and thermodynamic data for the prediction of the predominant conformation of organic molecules in solution: the example of the flavonoid rutin.

Conformational analyses of organic compounds in solution still represent a challenge to be overcome. The traditional methodology uses the relative energies of the conformations to decide which one is most likely to exist in the experimental sample. The goal of this work was to deepen the approach of conformational analysis of flavonoid rutin (a well-known antioxidant agent) in DMSO solution. The methodology we used in this paper involves expanding the sample configuration space to a total of 44 possible geometries, using Molecular Dynamics (MD) simulations, which accesses structures that would hardly be considered with our chemical perception, followed by DFT geometry optimizations using the ωB97X-D/6-31G(d,p) - PCM level of theory. Spectroscopic and thermodynamic analyses were done, by calculating the relative energies and nuclear magnetic resonance (1H-NMR) chemical shifts, comparing the theoretical and experimental 1H-NMR spectra (DMSO-d 6) and evaluating Mean Absolute Error (MAE). The essence of this procedure lies in searching for patterns, like those found in traditional DNA tests common in healthcare. Here, the theoretical spectrum plays the role of the analyzed human sample, while the experimental spectrum acts as the reference standard. In solution, it is natural for the solute to dynamically alter its geometry, going through various conformations (simulated here by MD). However, our DFT/PCM results show that a structure named 32 with torsion angles ϕ 1 and ϕ 2 manually rotated by approx. 20° showed the best theoretical-experimental agreement of 1H-NMR spectra (in DMSO-d 6). Relative energies benchmarking involving 16 DFT functionals revealed that the ωB97X-D is very adequate for estimating energies of organic compounds with dispersion of charge (MAE < 1.0 kcal mol-1, using ab initio post-Hartree-Fock MP2 method as reference). To describe the stability of the conformations, calculations of Natural Bonding Orbitals (NBO) were made, aiming to reveal possible intramolecular hydrogen bonds that stabilize the structures. Since van der Waals (vdW) interactions are difficult to be identified by NBO donations, the Reduced Density Gradient (RDG) were calculated, which provides 2D plots and 3D surfaces that describe Non-Covalent Interactions (NCI). These data allowed us to analyze the effect of dispersion interactions on the relative stability of the rutin conformations. Our results strongly indicate that a combination of DFT (ωB97X-D)-PCM relative energies and NMR spectroscopic criterion is a more efficient strategy in conformational analysis of organic compounds in solution.

Quantum Chemical Investigation of the Interaction of Thalidomide Monomeric, Dimeric, Trimeric, and Tetrameric Forms with Guanine DNA Nucleotide Basis in DMSO and Water Solution: A Thermodynamic and NMR Spectroscopy Analysis.

Thalidomide (TLD) was used worldwide as a sedative, but it was revealed to cause teratogenicity when taken during early pregnancy. It has been stated that the (R) enantiomer of TLD has therapeutic effects, while the (S) form is teratogenic. Clinical studies, however, demonstrated the therapeutic efficacy of thalidomide in several intractable diseases, so TLD and its derivatives have played an important role in the development and therapy of anticancer drugs. Therefore, it is important to know the molecular mechanism of action of the TLD, although this is still not clear. In what molecular interactions are concerned, it is known that drug molecules can interact with DNA in different ways, for example, by intercalation between base pairs. Furthermore, the ability of the TLD to interact with DNA has been confirmed experimentally. In this work, we report a theoretical investigation of the interaction of the R and S enantiomers of TLD, in its monomeric, dimeric, trimeric, and tetrameric forms, with guanine (GUA) DNA nucleotide basis in solution using density functional theory (DFT). Our initial objective was to evaluate the interaction of TLD-R/S with GUA through thermodynamic and spectroscopic study in dimethyl sulfoxide (DMSO) solvent and an aqueous solution. Comparison of the experimental 1H nuclear magnetic resonance (NMR) spectrum in DMSO-d6 solution with calculated DFT-PCM-DMSO chemical shifts revealed that TLD can undergo molecular association in solution, and interaction of its dimeric form with a DNA base ((TLD)2-GUA and (TLD)2-2GUA, for example) through H-bond formation is likely to take place. Our results strongly indicated that we must consider the plausibility of the existence of TLD associations in solution when modeling the complexation of the TLD with biological targets. This is new information that may provide further insight into our understanding of drug binding to biological targets at the molecular level.

Quantum chemical investigation of predominant conformation of the antibiotic azithromycin in water and DMSO solutions: thermodynamic and NMR analysis.

Azithromycin (AZM) is a macrolide-type antibiotic used to prevent and treat serious infections (mycobacteria or MAC) that significantly inhibit bacterial growth. Knowledge of the predominant conformation in solution is of fundamental importance for advancing our understanding of the intermolecular interactions of AZM with biological targets. We report an extensive density functional theory (DFT) study of plausible AZM structures in solution considering implicit and explicit solvent effects. The best match between the experimental and theoretical nuclear magnetic resonance (NMR) profiles was used to assign the preferred conformer in solution, which was supported by the thermodynamic analysis. Among the 15 distinct AZM structures, conformer M14, having a short intramolecular C6-OH … N H-bond, is predicted to be dominant in water and dimethyl sulfoxide (DMSO) solutions. The results indicated that the X-ray structure backbone is mostly conserved in solution, showing that large flexible molecules with several possible conformations may assume a preferential spatial orientation in solution, which is the molecular structure that ultimately interacts with biological targets.

The role of the basis set and the level of quantum mechanical theory in the prediction of the structure and reactivity of cisplatin.

In this article, we conducted an extensive ab initio study on the importance of the level of theory and the basis set for theoretical predictions of the structure and reactivity of cisplatin [cis-diamminedichloroplatinum(II) (cDDP)]. Initially, the role of the basis set for the Pt atom was assessed using 24 different basis sets, including three all-electron basis sets (ABS). In addition, a modified all-electron double zeta polarized basis set (mDZP) was proposed by adding a set of diffuse d functions onto the existing DZP basis set. The energy barrier and the rate constant for the first chloride/water exchange ligand process, namely, the aquation reaction, were taken as benchmarks for which reliable experimental data are available. At the B3LYP/mDZP/6-31+G(d) level (the first basis set is for Pt and the last set is for all of the light atoms), the energy barrier was 22.8 kcal mol(-1), which is in agreement with the average experimental value, 22.9 ± 0.4 kcal mol(-1). For the other accessible ABS (DZP and ADZP), the corresponding values were 15.4 and 24.5 kcal mol(-1), respectively. The ADZP and mDZP are notably similar, raising the importance of diffuse d functions for the prediction of the kinetic properties of cDDP. In this article, we also analyze the ligand basis set and the level of theory effects by considering 36 basis sets at distinct levels of theory, namely, Hartree-Fock, MP2, and several DFT functionals. From a survey of the data, we recommend the mPW1PW91/mDZP/6-31+G(d) or B3PW91/mDZP/6-31+G(d) levels to describe the structure and reactivity of cDDP and its small derivatives. Conversely, for large molecules containing a cisplatin motif (for example, the cDDP-DNA complex), the lower levels B3LYP/LANL2DZ/6-31+G(d) and B3LYP/SBKJC-VDZ/6-31+G(d) are suggested. At these levels of theory, the predicted energy barrier was 26.0 and 25.9 kcal mol(-1), respectively, which is only 13% higher than the actual value.

Superstructure based on ß-CD self-assembly induced by a small guest molecule.

The size, shape and surface chemistry of nanoparticles play an important role in cellular interaction. Thus, the main objective of the present study was the determination of the ß-cyclodextrin (ß-CD) self-assembly thermodynamic parameters and its structure, aiming to use these assemblies as a possible controlled drug release system. Light scattering measurements led us to obtain the ß-CD's critical aggregation concentration (cac) values, and consequently the thermodynamic parameters of the ß-CD spontaneous self-assembly in aqueous solution: Δ(agg)G(o) = -16.31 kJ mol(-1), Δ(agg)H(o) = -26.48 kJ mol(-1) and TΔ(agg)S(o) = -10.53 kJ mol(-1) at 298.15 K. Size distribution of the self-assembled nanoparticles below and above cac was 1.5 nm and 60-120 nm, respectively. The number of ß-CD molecules per cluster and the second virial coefficient were identified through Debye's plot and molecular dynamic simulations proposed the three-fold assembly for this system below cac. Ampicillin (AMP) was used as a drug model in order to investigate the key role of the guest molecule in the self-assembly process and the ß-CD:AMP supramolecular system was studied in solution, aiming to determine the structure of the supramolecular aggregate. Results obtained in solution indicated that the ß-CD's cac was not affected by adding AMP. Moreover, different complex stoichiometries were identified by nuclear magnetic resonance and isothermal titration calorimetry experiments.

(1) H NMR analysis of O-methyl-inositol isomers: a joint experimental and theoretical study.

Density functional theory (DFT) calculations of (1) H NMR chemical shifts for l-quebrachitol isomers were performed using the B3LYP functional employing the 6-31G(d,p) and 6-311 + G(2d,p) basis sets. The effect of the solvent on the B3LYP-calculated NMR spectrum was accounted for using the polarizable continuum model. Comparison is made with experimental (1) H NMR spectroscopic data, which shed light on the average uncertainty present in DFT calculations of chemical shifts and showed that the best match between experimental and theoretical B3LYP (1) H NMR profiles is a good strategy to assign the molecular structure present in the sample handled in the experimental measurements. Among four plausible O-methyl-inositol isomers, the l-quebrachitol 2a structure was unambiguously assigned based only on the comparative analysis of experimental and theoretical (1) H NMR chemical shift data. The B3LYP infrared (IR) spectrum was also calculated for the four isomers and compared with the experimental data, with analysis of the theoretical IR profiles corroborating assignment of the 2a structure. Therefore, it is confirmed in this study that a combined experimental/DFT spectroscopic investigation is a powerful tool in structural/conformational analysis studies.

Theoretical Investigation of Regiodivergent Addition of Anilines and Phenolates to p-Benzoquinone Ring.

Two different products were obtained by the regiodivergent reaction of benzoquinone derivatives with phenolates and anilines: 3-aryloxybenzoquinone and 2-phenylamino-3-bromobenzoquinone. Calculated density functional theory free energies of reaction values corroborate the experimental observation of the formation of the substitution product in the reaction with phenolates in acetonitrile and the product of addition/oxidation for the reaction with aniline in water. Calculated charges and Fukui functions are similar for C2 and C3 atoms, indicating an equal possibility to suffer a nucleophilic attack. The calculated energy barriers for nucleophilic attack steps indicated that the first steps of the substitution with phenolates and addition/oxidation with anilines are faster, which justifies the formation of the respective products. The natural bond order analysis for the transition states revealed that there is a strong interaction between lone pairs of N and O atoms and the πC2C3 * for the O → C2 and N → C3 attacks and a weak interaction for the O → C3 and N → C2 attacks, which also agrees with experimental observations.

Unveiling the Molecular Structure of Antimalarial Drugs Chloroquine and Hydroxychloroquine in Solution through Analysis of 1H NMR Chemical Shifts.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been standard antimalarial drugs since the early 1950s, and very recently, the possibility of their use for the treatment of COVID-19 patients has been considered. To understand the drug mode of action at the submicroscopic level (atoms and molecules), molecular modeling studies with the aid of computational chemistry methods have been of great help. A fundamental step in such theoretical investigations is the knowledge of the predominant drug molecular structure in solution, which is the real environment for the interaction with biological targets. Our strategy to access this valuable information is to perform density functional theory (DFT) calculations of 1H NMR chemical shifts for several plausible molecular conformers and then find the best match with experimental NMR profile in solution (since it is extremely sensitive to conformational changes). Through this procedure, after optimizing 30 trial distinct molecular structures (ωB97x-D/6-31G(d,p)-PCM level of calculation), which may be considered representative conformations, we concluded that the global minimum (named M24), stabilized by an intramolecular N-H hydrogen bond, is not likely to be observed in water, chloroform, and dimethyl sulfoxide (DMSO) solution. Among fully optimized conformations (named M1 to M30, and MD1 and MD2), we found M12 (having no intramolecular H-bond) as the most probable structure of CQ and HCQ in water solution, which is a good approximate starting geometry in drug-receptor interaction simulations. On the other hand, the preferred CQ and HCQ structure in chloroform (and CQ in DMSO-d6) solution was assigned as M8, showing the solvent effects on conformational preferences. We believe that the analysis of 1H NMR data in solution can establish the connection between the macro level (experimental) and the sub-micro level (theoretical), which is not so apparent to us and appears to be more appropriate than the thermodynamic stability criterion in conformational analysis studies.

DFT study of the full catalytic cycle for the propene hydroformylation catalyzed by a heterobimetallic HPt(SnCl3)(PH3)2 model catalyst.

DFT calculations were carried out to study the full catalytic cycle for the hydroformylation of propene, catalyzed by the heterobimetallic model catalyst trans-Pt(H)(PH(3))(2)(SnCl(3)). Before the study of the full catalytic cycle, the performance of six pure GGA, one GGA with inclusion of dispersion corrections, four hybrid-GGA, and three meta-GGA exchange correlation functional to describe a model reaction promoted by Pt-Sn catalyst were assessed. It is shown that the BP86 and GPW91 functionals, using extended basis set, provides reliable energetic results when compared with the CCSD(T) calculations. All intermediates and transition states along the elementary steps of the entire catalytic cycle were located and the energies involved in the catalytic cycle calculated using BP86 functional. The solvent effects along the entire catalytic cycle were evaluated using the polarizable continuum model. In contrast with the rhodium catalysts, the regioselectivity of the hydroformylation is set at the carbonylation step. The hydrogenolysis is the rate determining step of the entire cycle, with the activation energy of approximately 21 kcal mol(-1) in agreement with the experimental value of approximately 25 kcal mol(-1). The trans effect of the SnCl(3)(-) ligand seems to be pronounced only in the first step of the catalytic cycle, facilitating the insertion of the olefin into the Pt-H bond trans to it. The analysis of the stationary points obtained along each elementary step of the catalytic cycle is carried out separately and discussed. The BP86/cc-pVTZ/SBKJC results shows that the pathway leading to the linear aldehyde is preferred, being in agreement with the experimental findings.

Determination of Anticancer Zn(II)-Rutin Complex Structures in Solution through Density Functional Theory Calculations of 1H NMR and UV-VIS Spectra.

Coordination compounds formed by flavonoid ligands are recognized as promising candidates as novel drugs with enhanced antioxidant and anticancer activity. Zn(II)-Rutin complexes have been described in the literature and distinct coordination modes proposed based on 1H NMR/MS and IR/UV-VIS experimental spectroscopic data: 1:1/1:2 (Zn(II) binding to A-C rings) and 2:1 (Zn(II) binding to A-C-B rings) stoichiometry. Aiming to clarify these experimental findings and provide some physical insights into the process of complex formation in solution, we carried out density functional theory calculations of NMR and UV-VIS spectra for 25 plausible Zn(II)-Rutin molecular structures including solvent effect using the polarizable continuum model approach. The studied complexes in this work have 1:1, 1:2, 2:1, and 3:1 metal-ligand stoichiometry for all relevant Zn(II)-Rutin configurations. The least deviation between theoretical and experimental spectroscopic data was used as an initial criterion to select the probable candidate structures. Our theoretical spectroscopic results strongly indicate that the experimentally suggested modes of coordination (1:2 and 2:1) are likely to exist in solution, supporting the two distinct experimental findings in DMSO and methanol solution, which may be seen as an interesting result. Our predicted 1:2 and 2:1 metal complexes are in agreement with the experimental stoichiometry; however, they differ from the proposed structure. Besides the prediction of the coordination site and molecular structure in solution, an important contribution of this work is the determination of the OH-C5 deprotonation state of rutin due to metal complexation at the experimental conditions (pH = 6.7 and 7.20). We found that, in the two independent synthesis of metal complexes, distinct forms of rutin (OH-C5 and O(-)-C5) are present, which are rather difficult to be assessed experimentally.

1H and 195Pt NMR prediction for inclusion compounds formed by cisplatin and oxidized carbon nanostructures.

Prediction of NMR chemical shifts can assist experimentalists in the characterization of drug delivery systems based on carbon nanocomposites. Chemical shifts are strongly correlated to the nucleus position and its chemical neighborhood. Therefore, to predict structures and NMR properties of complex chemical models, choosing a more consistent theoretical level capable of providing more realistic results and moderate computational demand is a major challenge. In this work, we predicted the NMR spectra of inclusion compounds formed by cisplatin (cDDP) and an oxidized carbon nanotube (CNTox) and nanocone (CNCox) considered by specialists as potential drug delivery systems. The 195Pt NMR chemical shifts calculated at the DFT level with the new relativistic NMR-DKH basis set were -2314 ppm and -2192 ppm for cDDP@CNTox and cDDP@CNCox complexes, respectively, which are both high-field shifted relative to the free cDDP (-2110 ppm). 1H NMR chemical shifts are also sensitive to the inclusion process. The H (NH3) signals are found on average at +4.3 (cDDP), -5.1 (cDDP@CNTox) and +6.6 ppm (cDDP@CNCox). Interestingly, despite the similar inclusion modes in CNTox and CNCox cavities, the 1H NMR shifts were in opposite directions. A possible reason might be the higher stability of cDDP@CNTox (ΔE F = -19.9 kcal mol-1) than that of cDDP@CNCox (ΔE F = -5.7 kcal mol-1), which suggests a short guest-host contact in the former and consequently, a more efficient shielding of hydrogen atoms due to the electron-rich carbon structure. These results may be helpful as comparison data in the NMR spectra assignment in solution and the inclusion compounds' structural elucidation.

Structure and stability of (alpha-CD)3 aggregate and OEG@(alpha-CD)3 pseudorotaxane in aqueous solution: a molecular dynamics study.

Empty linear associations accounting for three alpha-CD units and their corresponding pseudorotaxanes have been studied by means of long length molecular dynamics (MD) simulations in a vacuum and in aqueous solution. Results from MD for empty sequences lead to a quite stable arrangement formed by three mutually perpendicular cyclodextrin (CD) units named here as 3P. In such a spatial arrangement, the van der Waals term in the force field is pronounced, accounting for almost 40% of the association energy, which ensures the noticeable stability of the 3P association even in aqueous media. In addition, it can be stated that only the presence of the oligomer forces the CD units to acquire an almost linear association. Mutually perpendicular-based arrangements are the most favorable spatial disposition in aqueous media. We believe this work is the first step toward a more ambitious study including very large CD sequences, aiming to understand the association process in aqueous solution at a molecular level.

Molecular dynamics of carbon nanohorns and their complexes with cisplatin in aqueous solution.

The medication with Pt-based antitumor drug cisplatin has demonstrated effective results against cancer cells, despite the severe side effects due to the high toxicity associated with the low selectivity of these anticancer agents. An alternative to overcome or decrease the side effects is to use drug delivery systems, which can carry high doses of the anticancer drug and promote its slow and targeted release to the tumor sites. Herein, we used molecular dynamics to study prototypes of the complexes formed by the encapsulated cisplatin and carbon nanohorns (CNH), with the purpose to characterize its structures and dynamical behavior in aqueous solution, an important feature to assess the potentiality of using CNH as carrier systems. The results indicated the presence of up to 36 water molecules inside the empty CNH cavity, depending on the cone angle and the presence of the cisplatin. Some of these solvent molecules are expelled out to the bulk upon cisplatin inclusion, although more than 10 molecules remain even for the narrow structures. Moreover, the calculated binding free energy (ΔbG) pointed out that the inclusion complexes formation between CNH structures and up to two cisplatin molecules was thermodynamically favorable in aqueous media, which suggests the potentiality of these carbon nanostructures as drug carriers. For the most likely and narrow host structure the average ΔbG was -92.0 kcal mol-1 for inclusion of two cisplatin, with most of the complex stability coming from the van der Waals contribution.

Supramolecular self-assembly of cyclodextrin and higher water soluble guest: thermodynamics and topological studies.

The supramolecular interactions between Imipramine hydrochloride (IMI), a tricyclic antidepressant, and beta-cyclodextrin (betaCD) have been investigated by experimental techniques and theoretical calculations. The association between these molecules might be lead to a host/guest compound, in which the physical chemistry properties of the guest molecule, such as high solubility, can be decreased. These new properties acquired by the inclusion phenomena are important to develop a strategy for pharmaceutical formulation. Nuclear magnetic resonance and horizontal attenuated total reflectance provided relevant information on the complex stoichiometries and the sites of interactions between the host and guest molecules. Stoichiometries of 1:2, 1:1, and 2:1 betaCD/IMI have been detected in solution. Self-diffusion coefficient and dynamic light scattering analysis provided information on the self-aggregation of the complex. Also, isothermal titration calorimetry studies indicated the existence of equilibrium between different complexes in solution. In order to determine the preferred arrangement for the inclusion complex formed by the IMI molecule and betaCD, theoretical calculations were performed. Of all proposed supramolecular structures, the 2:1 betaCD/IMI complex was calculated to be the most energetically favorable, in both gas and aqueous phases. The calculations indicated that the intermolecular hydrogen bonds involving the hydroxyl groups of betaCD play a major role in stabilizing the supramolecular 2:1 structure, corroborating experimental findings.