Modelización molecular de complejos de inclusión de ciclodextrinas con acetazolamida

Las ciclodextrinas (CDs) son oligomeros cíclicos constituidos por seis, siete, ocho o mas unidades de α-D-glucopiranosa unidos por enlaces 1-4. Se obtienen por una reacción de degradación de la enzima ciclodextrin-glucotransferasa sobre el almidón. Tanto las CDs naturales como sus diferentes derivados poseen la capacidad de formar compuestos de inclusión con una amplia variedad de especies químicas, modificando las propiedades fisicoquímicas de las mismas de forma ventajosa. Este fenómeno constituye la base de múltiples aplicaciones en el campo de la Medicina, Farmacia, Química, Agricultura, Alimentación y Medio ambiente, entre otras. En la actualidad, en nuestro departamento se están estudiando diferentes aspectos de la complejacion de ACZ con CDs, con objeto de aumentar su solubilidad y permitir la incorporación de una mayor concentración de fármaco en el desarrollo de un medicamento solución oftalmica para tratamiento del glaucoma. En este trabajo, intentaremos profundizar el conocimiento de las interacciones entre ACZ y una serie de CDs, en concreto β-CD e hidroxipropil β-CD (HP-b-CD) al formar complejos de inclusión a través de modelización molecular (in silico), mediante el uso de software de modelización molecular. Para ello, se acudió al empleo de mecánica molecular (campo de fuerza MM+ en el vacio), complementándose con la aplicación de métodos semiempiricos de mecánica cuántica (Parametric Model 3). Para la correcta realización de esta técnica y así poder hallar el mínimo global de energía, fue necesario partir de estructuras de mínima energía de los monómeros (fármacos y CDs). Los resultados obtenidos sugieren la formación de complejos estables y por tanto viables, para los cuales se observó que los puentes de hidrogeno jugaban un papel muy importante. En general, los valores de diferencial de energía HOMO-LUMO se hallaron en buena correlación con los valores de energía de complejacion e interacción confirmando también la estabilidad de los complejosUniversidad de Sevilla. Grado en Farmaci

Chiral separation of ketoconazole and itraconazole anti-fungal drugs using experimental and computational approaches

Drugs with multiple chiral centers were observed as very effective for treating various diseases. However, the enantiomeric resolution of multiple chiral center racemates is not much developed compared to racemates having a single asymmetric center. This work aimed to develop a chiral separation method for antifungal drugs using electrokinetic chromatography (EKC) and to elucidate mechanism of enantioseparation using a computer-aided molecular modelling study. Two azole antifungal drugs were selected namely ketoconazole and itraconazole, which consists of two and three chiral centers, respectively. The separation for ketoconazole was achieved using heptakis (2,3,6-tri-O-methyl)-ß-cyclodextrin (TM-ß-CD), a commonly used chiral selector, as it is relatively inexpensive and has a low UV absorbance in addition to an anionic surfactant, sodium dodecyl sulfate. The optimum conditions for chiral separation of ketoconazole was achieved using 10 mM phosphate buffer at pH 2.50 containing 20 mM TM-ß-CD, 5 mM SDS, and 1.0% (v/v) methanol with an applied voltage of 25 kV at 25°C with a 5-s hydrodynamic injection time at 50 mbar. The four ketoconazole stereoisomers were successfully resolved within 17 min (total analysis time was 28 min including capillary conditioning). The migration time precision of this method was examined to give a repeatability and reproducibility with RSDs = 5.80% (n = 3) and RSDs = 8.88% (n = 9), respectively. A computational study, using quantum mechanics calculations with AutoDock and semi-empirical PM3 calculations, were used to predict the enantiodiscrimination of ketoconazole enantiomers. A Density Functional Theory (DFT) single-point calculation at the level of B3LYP/6-311G (d,p) was performed for the PM3-optimized complexes to obtain more accurate binding energy and also electronic structures of the complexes. Molecular docking and DFT were simulated to predict the enantioresolution of itraconazole with two types of cyclodextrins (CDs), TM-ß-CD and (2-hydroxylpropyl)-?-cyclodextrin (HP-?-CD). The difference in energies of the inclusion complexes between the enantiomers and CD is a measure of chiral discrimination, which results in the separation of the enantiomers in the experimental studies. The dual-CD and triple-CD methods were developed for chiral separation of itraconazole using EKC. Highly sulfated ß-cyclodextrin (S-ß-CD), (2-hydroxylpropyl)-ß-cyclodextrin (HP-ß-CD), TM-ß-CD and HP-?-CD were screened as possible chiral selectors for enantioseparation of itraconazole. The enantioseparation of itraconazole was achieved using 10 mM phosphate buffer solution at pH 3.62 containing a mixture of 10 mM of each HP-ß-CD, TM-ß-CD and HP-?-CD and an applied voltage of 25 kV at 25°C. Both computational and experimental investigations complement each other prior to chiral recognition mechanism. Combination of molecular modelling and capillary electrophoresis appears as a new emerging method for chiral analysis of pharmaceutical drugs

Bioinformatics

This book is divided into different research areas relevant in Bioinformatics such as biological networks, next generation sequencing, high performance computing, molecular modeling, structural bioinformatics, molecular modeling and intelligent data analysis. Each book section introduces the basic concepts and then explains its application to problems of great relevance, so both novice and expert readers can benefit from the information and research works presented here

49th Rocky Mountain Conference on Analytical Chemistry

Final program, abstracts, and information about the 49th annual meeting of the Rocky Mountain Conference on Analytical Chemistry, co-endorsed by the Colorado Section of the American Chemical Society and the Rocky Mountain Section of the Society for Applied Spectroscopy. Held in Breckenridge, Colorado, July 22-26, 2007