Molecular modeling study of the recognition mechanism and enantioseparation of 4-hydroxypropranolol by capillary electrophoresis using carboxymethyl-ß-cyclodextrin as the chiral selector.

The purpose of this paper was to study at the molecular level the enantioseparation mechanism of 4-hydroxypropranolol (4-OH-Prop) with carboxymethyl-ß-cyclodextrin (CM-ß-CD) using a sequential methodology which included molecular dynamics simulations (MD), and Parametric Model 3 (PM3) semiempirical and density functional theory (DFT) calculations. A systematic structural analysis indicated that hydrogen bonds formed between the host and guests play a major role in the complex stabilization. The inclusion complex (+)-(R)-4-OH-Prop/CM-ß-CD showed three strong intermolecular hydrogen bonds. Moreover, the guest inclusion process made from a wider CD rim presented lower energies (interaction and Gibbs free energy) in comparison to the inclusion made by a narrower CD rim in both gas and aqueous phases. This difference in energies of drug/CM-ß-CD inclusion complexes is probably a measure of chiral discrimination, which results in the separation of the enantiomers and the distinct separation factors as observed in previous experimental findings. Comparing the experimental results of the separation of 4-OH-Prop enantiomers by capillary electrophoresis (CE), the proposed theoretical model demonstrated good capability to predict chiral separation of 4-OH-Prop enantiomers as well as the qualitative estimative of chiral recognition mechanism.

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.

Structural and Electronic Characterization of a Photoresponsive Lanthanum(III) Complex Incorporated into Electrospun Fibers for Phosphate Ester Catalysis.

Herein, we present the light-induced synthesis and characterization of a La3+/spiropyran derivative complex (LaMC) and its application as a catalyst when incorporated into electrospun polycaprolactone (PCL) fibers. In addition to experimental methods, computational calculations were also essential to better understand the structure and electronic characteristics of LaMC. The LaMC complex was identified as a 10-coordinated structure with the La3+ ion coordinated by four oxygens from the phenolate and the carbonyl of the carboxyl acid group from both MC ligands and by six oxygens from three nitrate ligands. In addition, LaMC was capable of getting reversibly isomerized by UV or visible light cycling. All PCL fibers were successively obtained, and their morphologies, surface properties, and catalytic behavior were studied. Results showed that PCL/LaMC fibers were capable of catalyzing bis(2,4-dinitrophenyl)phosphate degradation efficiently. Complete hydrolysis was accomplished in only 1.5 days relative to the half-life time of 35 days for the uncatalyzed hydrolysis at pH 8.1 and 25 °C.

Thermodynamic compatibility between cyclodextrin supramolecular complexes and surfactant.

Supramolecular structures based on cyclodextrins have been extensively used for drug delivery systems over decades. However, combining host and guest molecules in a pharmaceutical formulation is not a trivial process, being one of the majors concern the inclusion complex compatibility with other excipients presented in the final formulation. Herein, experimental and theoretical calculations were used to investigate the competition of sodium dodecyl sulfate (SDS) with atenolol (ATE) or losartan (LOS), antihypertensive drugs widely used in the treatment of hypertension. Our findings, using nuclear magnetic resonance and isothermal titrations calorimetry experiments and molecular dynamic simulations demonstrated that LOS remain included into CD cavity after excipient (SDS) addition, which was not verified for ATE ternary system, being the drug displaced by SDS molecule.

Monte Carlo simulation of cisplatin molecule in aqueous solution.

The Lennard-Jones (12-6) parameters were obtained for all atoms of cisplatin molecule using the ab initio quantum mechanical potential energy surface for the water-cisplatin interaction as reference data. The parameters found were (epsilon/kcal.mol(-1) and sigma/angstroms) 1.0550, 3.6590 (Pt); 0.0381, 4.6272 (Cl); 0.0455, 3.3783 (N); and 0.0185, 0.0936 (H) and provided very good results for the description of the aqueous solution of cisplatin through Monte Carlo simulation. From statistical analysis of solute-solvent interactions, we observed that the NH3 groups are involved in 53% of the calculated hydrogen bonds with a significant contribution from chlorides (41%) and only 6% involving the Pt center. This is in agreement with the expected behavior for such molecules. Two hydration shells with 22 and 81 water molecules, respectively, centered around 4.6 and 7.3 angstroms were found from the center of mass pair correlation function analysis. The cisplatin atomic Lennard-Jones parameters are reported for the first time, and they might be useful for studying the structure, properties, and processes of cisplatin-like molecules in aqueous solution, including explicitly the solvent effect.

Inclusion complex thermodynamics: The ß-cyclodextrin and sertraline complex example.

Thermodynamic properties for ß-cyclodextrin-Sertraline inclusion process was calculated at the density functional theory (DFT) level using the PBE0 functional with 6-31G(d,p), 6-31++G(d,p) and 6-311++G(2df,p) basis sets. Electron correlation was evaluated through Møller-Plesset second-order perturbation theory (MP2). The standard statistical thermodynamic approach was used to assess the entropic contribution to the Gibbs free energy value. According to our results, inclusion of hydration waters to describe the reactants and products in the complex formation reaction model is crucial in order to reproduce the experimental data and seems very coherent with basics thermodynamics yielding good agreement with experiment.

Multi-equilibrium system based on sertraline and ß-cyclodextrin supramolecular complex in aqueous solution.

Sertraline (SRT) is a widely used antidepressant whose poor solubility in water limits its oral applicability. Thus, the aim of this work was the evaluation of a multi-equilibrium system based on ß-cyclodextrin (ßCD) and SRT. The inclusion compounds (ICs) were investigated by infrared spectroscopy, isothermal titration calorimetry (ITC) and (1)H and 2D ROESY nuclear magnetic resonance experiments. SRT solubility was predicted in vitro in water and biomimetic fluids. The SRT in presence of ßCD at 1:1 and 1:2 molar ratios was more soluble than free SRT in all biomimetics media investigated. The FTIR-HATR showed that ßCD νC-O-C stretching band was reduced in presence of SRT, suggesting the interactions between them. Additionally, titration process and Job's plot provided information on the ICs stoichiometry and evidenced the multi-equilibrium coexistence in aqueous solution. According to the ITC, SRT:ßCD interaction process was spontaneous and exothermic with a high affinity binding constant (K=14,726 M(-1)). Additionally, the stoichiometry coefficient (n) was 1.63, which was comparable to that found by FITR-HATR. The (1)H and 2D ROESY verified multiple SRT sites included into the host cavity. Theoretical calculations depicted the relative energy of different proposed ICs structures, in which the 1:2 IC was the most stable.

Theoretical study of the potential energy surface for the interaction of cisplatin and their aquated species with water.

In this work, a systematic study of the interaction of neutral cisplatin ([Pt(NH(3))(2)Cl(2)]) and their charged aquated species ([Pt(NH(3))(2)Cl(H(2)O)](+) and [Pt(NH(3))(2)(H(2)O)(2)](2+)) with water was carried out. The potential energy surface (PES) was analyzed by considering 35 spatial orientations for the interacting species. The calculations were performed at various levels of theory including Moller-Plesset fourth order perturbation theory and density functional theory (DFT-B3LYP) using extended basis sets. Lennard-Jones (12-6) plus Coulomb classical potential was also used to assess the repulsion-dispersion and electrostatic contributions. The effect of atomic charges on the interaction energies is discussed using Mulliken, charges from electrostatic potential grid method and natural bond orbital schemes. The outcomes show that the electrostatic term plays a primary role on the calculation of interaction energies, with the absolute values of atomic charges from different approaches significantly affecting the overall interaction. Unusual results were revealed by basis set superposition error calculations for the structures located on the platinum-water PES.