Predicting Complexation Thermodynamic Parameters of β-Cyclodextrin with Chiral Guests by Using Swarm Intelligence and Support Vector Machines

The Particle Swarm Optimization (PSO) and Support Vector Machines (SVMs) approaches are used for predicting the thermodynamic parameters for the 1:1 inclusion complexation of chiral guests with β-cyclodextrin. A PSO is adopted for descriptor selection in the quantitative structure-property relationships (QSPR) of a dataset of 74 chiral guests due to its simplicity, speed, and consistency. The modified PSO is then combined with SVMs for its good approximating properties, to generate a QSPR model with the selected features. Linear, polynomial, and Gaussian radial basis functions are used as kernels in SVMs. All models have demonstrated an impressive performance with R2 higher than 0.8

Modified aqueous mobile phases: A way to improve retention behavior of active pharmaceutical compounds and their impurities in liquid chromatography

Most commonly used analytical technique for determination of active pharmaceutical ingredients and their impurities in quality control throughout all phases of drug research, development and manufacture is definitely reversed-phase high performance liquid chromatography (RP-HPLC). However, pharmaceutical industry professionals are often faced with various challenges in RP mode, which cannot be resolved with common variations in the composition of the mobile phase. These challenges often occur when analyzing compounds that contain basic ionizable groups, possess large differences in polarities and require consumption of high amounts of toxic organic solvents. Among available strategies for addressing the aforementioned issues, the most convenient one includes RP-HPLC mobile phase modifications by an addition of the proper chemical compounds. In that respect, RP-HPLC method can be easily adapted to the needs of the analysis without time-consuming and expensive equipment procurement. In this review the chaotropic chromatography, micellar liquid chromatography, and cyclodextrin modified RP-HPLC systems are presented and discussed in details. Special attention is devoted to the theoretical background, the possibility of retention modeling and applications in various fields of pharmacy, as well as their prospective in further research

Cyclodextrins: Past and Present

Cyclodextrins (CDs) are cyclic oligosaccharides produced by enzymatic degradation of starch. The most common CDs are the main natural ones, α, β and γ, which are constituted of 6, 7 and 8 glucopyranose units, respectively. The CD structure forms a torus or doughnut ring and the molecule actually exists as a truncated cone. The outer side of the toroid is hydrophilic in nature due to the hydroxyl groups of the glucopyranose units while the internal cavity is relatively apolar. Thus, CDs have a high potential to entrap entirely or partially a wide variety of compounds in a process known as complexation. This gives them new physico-chemical properties and characteristics. The main applications of CDs in drug formulation rely on CD complexation and include the protection of easily oxidizable molecules or the improvement of aqueous solubility. The use of CDs in analytical chemistry is based on his host-guest recognition property, known as supramolecular complex formation. Currently, CDs are successfully used in molecular recognition-based methods like chromatographic separations, spectroscopic and electroanalyses. Quiral analytical separations are a CD area of special relevance. In this work, attention is paid to more recent references, especially to selected reviews

Nuevas aportaciones al desarrollo de modelos QSAR/QSPR para la predicción de la mutagenicidad de contaminantes ambientales y su interacción con sustancias activas presentes en el medio

Se estudió mediante modelos QSAR, la posible mutagenicidad de sustancias presentes en el medio ambiente como los ácidos haloacéticos (derivados de la cloración del agua) y los carbonilos alfa, beta insaturados (sobre todo los empleados como monómeros para la preparación de materiales dentales de restauración) y su posible interacción con la beta ciclodextrina, la cual está presente como excipiente en productos farmacéuticos y como estabilizador de aromas, colorantes y algunas vitaminas en alimentos. Como resultado de este estudio pudimos destacar: -El ácido fluoroiodoacético y difluoroiodoacético podrían ser mutagénicos debido a los valores de potencia mutagénica obtenidos con los modelos desarrollados. Sustancias que podrían encontrarse en aguas fluoradas ricas en ioduro/bromuro. Además es posible que estén presentes en aguas fluoradas ricas en bromuro/ioduro hecho que pondría en duda la necesidad de fluorar el agua potable. - Sustancias comúnmente empleadas como monómeros dentales presentaron predicciones negativas para el ensayo de Ames y un carácter mutagénico para el ensayo con células de mamífero, a excepción del UDMA (Uretil dimetacrilato). - Respecto a la posible interacción de estas sustancias con la beta-ciclodextrina, los ácidos haloacéticos presentan valores de complejación inferiores a los que normalmente presentan fármacos o componentes de los alimentos, por lo que es de esperar que la interacción entre los ácidos haloacéticos y la beta-CD sea de escasa importancia. En cuanto a los monómeros dentales hay que resaltar que sustancias como el TEGDMA, 1,6-ADMA, 1,8-ADMA, GMR, MEPC y 6-HHMA, predichos como mutagénicos, presentan valores de complejación superiores a los que presentan fármacos o componentes de los alimentos. Por lo tanto, estas sustancias podrían desplazar de sus complejos a fármacos o componentes de los alimentos pudiéndose llegar a algún tipo de interacción.Farmaci

MASS SPECTROMETRIC ANALYSIS OF LIGNIN MODEL COMPOUNDS: FUNDAMENTAL INVESTIGATIONS OF IONIZATION AND SUPRAMOLECULAR INTERACTIONS FOR LIGNOCELLULOSIC BIOMASS APPLICATIONS

Lignocellulosic biomass is pivotal for the development of renewable energy sources and materials essential to mitigate the exploitation of fossil fuels causing climate change and environmental pollution issues. The conversion of biomass into fuel requires the hydrolysis of cellulose and a biproduct of this process is the isolation of millions of tons of lignin as biorefinery waste. Lignin is a complex high molecular weight polymer whose structure remains undefined and critically limits potential industrial applications of lignocellulosic biomass. The advancement of analytical methods for structural elucidation of lignin and its ensemble of phenolic compounds is therefore essential to advance this field. While a variety of degradation processes have been developed to study the structure of lignin, depolymerization compositions are complex and prone to repolymerization. As a result, the primary strategy to mitigate difficulties is the development of model systems based on native lignin linkages. Analytical methods for lignin and lignin model compounds are critically limited due to the lack of commercially available compounds and the complex nature of the lignin polymer. While a variety of analytical methods play an integral role in developing our understanding of lignin, only mass spectrometry can provide exact information on the substructure of lignin, the sequence of monolignols, and linkage types. In this dissertation, the supramolecular interactions of a variety of model lignin monomers and dimers are fundamentally characterized to improve mass spectrometric analysis and potential applications of lignin as a renewable source of valuable phenolics. Mass spectrometry (MS) requires the conversion of analytes into detectable gas-phase ions that are manipulated by electric fields for mass to charge (m/z) analysis, and the most widely used ionization technique for biological compounds is electrospray ionization (ESI). The primary challenge facing ESI-MS analysis of lignin is ionization because lignin compounds do not readily accept protons for positive mode analysis and negative mode analysis causes destabilization and in-source fragmentation. While protonation is unsuccessful, lithium adduct cationization has recently been discovered as a promising method for ESI-MS sequencing of lignin compounds. The equilibrium of ion transfer reactions is governed by gas-phase basicity, a fundamental measure of the thermodynamics of supramolecular interactions that define ionization success. Consequently, the gas-phase lithium cation basicity of synthetic monolignols and dimers were characterized by ESI-MS to improve sequencing techniques and future applications of lithium adduction. Lignin also presents a challenge in biomass processing due to its inhibition of the enzymatic hydrolysis of cellulose for biofuel production. Sustainable and economically viable processes are still under development since current pre-treatment methods for the removal of lignin generates toxic compounds and are unsuitable for commercial applications. Supramolecular guest-host interactions have the potential to isolate lignin compounds from biomass fractions through the formation of inclusion complexes and the development of selective materials. In this work a cyclodextrin host was selected based on its remarkable ability to encapsulate guest molecules, non-toxicity, and availability on the industrial scale. The formation constant (K) or binding strength between guest and host was evaluated for lignin model dimers with cyclodextrin by lithium adduct ESI-MS for comparison with our collaborators ITC and computational results. The retention of electrostatically bound complexes during the ESI-MS process and lithium adduct impacts were also extensively evaluated. Lignin compounds and metabolites have also shown biological activity and therefore the separation of diastereomers is of interest for pharmaceutical and medicinal applications. To advance biological studies, the success of chromatographic separations (HPLC) of lignin model dimers and their diastereomers were evaluated. The separative method was coupled to MS with post-column lithium adduct ionization to identify lignin dimers. Novel determinations of lignin dimer partition coefficients are also presented, a measure of hydrophobicity important for biological studies and chromatographic method development. This dissertation supports the development of analytical methods for lignin degradation products and secondary metabolites (lignans) that have shown exciting biological activities. Fundamental characterizations of ionization for mass spectrometry are important for a variety of analytical applications including the sequencing of lignin compounds, gas-phase thermodynamic studies, and the optimization of separation techniques. Continued improvements in this field will reduce our exploitation of fossil fuels and advance the sustainable conversion of lignocellulosic biomass into biofuels and platform aromatic chemicals

Computational approaches in supramolecular chemistry with a special focus on virtual screening

Within this thesis novel computational tools for the rational design of synthetic host-guest complexes (SHGC) were developed and applied that employ the concepts of efficient virtual screening (VS) approaches. The first part describes the development of a fast structure prediction tool for flexible SHGC. The tool was validated on a test dataset comprising crystallographically determined SHGC. In nine of ten cases near-native solutions were generated. The tool can be applied for VS. In the second part of the thesis computational techniques were applied for designing SHGC based on ß-cyclodextrins (ß-CD). We performed a structure-based inverse virtual screening for identifying modified ß-CDs as receptors for the anticancer drug camptothecin (CPT). Six of the proposed receptors exhibited binding affinities which were significantly higher than for any other CPT-receptor. Furthermore, we applied a combination of a similarity-based virtual screening technique with a regression model (RM) for identifying novel high affinity guest molecules of ß-CD. Ten of the proposed guest molecules exhibited a binding free energy of lower than -20 kJ/mol. The last chapter describes a comparison of regression methods regarding their ability to generate predictive RM for thermodynamical parameters (dG, dH and dS) of ß-CD-guest complexes. dG could be predicted in good agreement with experimental values, none of the methods led to comparably good predictive models for dH. dS appears almost unpredictable.Im Rahmen dieser Arbeit wurden rechnergestützte Verfahren (RGV) zum gezielten Entwurf von synthetischen Wirt-Gast Komplexen (SWGK) entwickelt und eingesetzt. Dabei wurde ein Fokus auf schnelle virtuelle Screening (VS) Verfahren gelegt. Der erste Teil beschreibt die Entwicklung eines Programms zur schnellen Strukturvorhersage von flexiblen SWGK. Das Programm wurde auf einem Testdatensatz an kristallographisch vermessenen SWGK validiert. Für neun von zehn SWGK wurden nativ-ähnliche Lösungen gefunden. Das Programm kann für VS eingesetzt werden. Der zweite Teil der Arbeit behandelt RGV zum gezielten Entwurf von ß-Cyclodextrin (ß-CD) Komplexen. Mit Hilfe eines strukturbasierten inversen VS wurden sechs modifizierte ß-CD-Rezeptoren für den Krebsarzneistoff Camptothecin (CPT) gefunden, die deutlich höhere Bindungsaffinitäten zu CPT aufwiesen als alle bislang bekannten CPT-Rezeptoren. Zur Identifizierung neuer hochaffiner Gäste von ß-CD wurde ein ähnlichkeitsbasiertes VS Verfahren in Kombination mit einem Regressionsmodell (RM) eingesetzt. Zehn der mit Hilfe dieses Verfahrens vorgeschlagenen Moleküle wiesen eine Bindungsenergie von unter -20 kJ/mol auf. Das letzte Kapitel beschreibt einen Vergleich von drei Regressionsverfahren. Es wurde die Fähigkeit untersucht, vorhersagekräftige RM für thermodynamische Parameter (dG, dH und dS) von ß-CD-Gast-Komplexen zu generieren. dG konnte mit allen Methoden sehr gut vorhergesagt werden, während dH nur begrenzt und dS unzureichend vorhersagbar war

Molecular modelling on cyclodextrin inclusion complexes

Es wurden ab initio und Dichtefunktionaltheorie-Berechnungen auf entsprechend hohem theoretischen Niveau an Cyclodextrinen und Cyclodextrin-Komplexen durchgeführt. Als Ergebnis einer Untersuchung über den Einfluss der verwendeten Theorie auf die Größe der BSSE (basis set superposition error)-Korrektur auf die berechneten Energien im Modellsystem Wasser-Methanol konnte gezeigt werden, dass die Korrektur-Energie mit Verbesserung des Basissatzes abnimmt. Systematische Untersuchungen der Abhängigkeit bestimmter geometrischer Parameter von Malonaldehyd im Hinblick auf das Niveau der verwendeten Theorie ergaben, dass Optimierungen mit den theoretischen Modellen DFT B3LYP/6-31G(d,p) und MP2/6-311+G(d,p) Geometrien ergeben, die in ausgezeichneter Übereinstimmung mit den gefundenen experimentellen Ergebnissen stehen. Eine Untersuchung der Komplexbildung zwischen β-Cyclodextrin und der Aminosäure Alanin mittels DFT B3LYP/6-31G(d,p)-Rechnungen bestätigte die Annahme, dass β-Cyclodextrin als chiraler Selektor der beiden enantiomeren Formen des Alanins fungieren kann. Als wichtigstes Ergebnis einer Untersuchung verschiedener neutraler und anionischer Einschlussverbindungen von Meloxicam und β-Cyclodextrin mittels DFT B3LYP/6-31G(d,p)-Rechnungen wurde gefunden, dass Wasserstoffbrückenbindungs-Wechselwirkungen an der Komplexbildung beteiligt sind und maßgeblich zur Stabilisierung der jeweiligen Komplexe beitragen. Die Ergebnisse all dieser Untersuchungen wurden in den folgenden fünf Veröffentlichungen zusammengefasst und angewendet: “Homodromic Hydrogen Bonds in Low-Energy Conformations of Single Molecule CDs”, “On the Structure of Anhydrous β-CD”, “Density Functional Calculations on CDs”, “Molecular Dynamics Simulations and Quantum Chemical Calculations on β-CD-Spironolactone Complex”, und “Density functional calculations on meloxicam-β-cyclodextrin Inclusion Complexes”Ab initio and Density Functional Theory (DFT) computations at an appropriate high level of theory have been performed on cyclodextrins (CDs) and CD complexes. As a result of an investigation of the impact of the theory used on the magnitude of the basis set superposition error (BSSE) correction energy on the calculated energies of the model system water-methanol-dimer it could be shown that as the basis set is improved the BSSE energy is reduced. Systematic investigations on the dependence of several geometric parameters of malonaldehyde on the level of theory used led to the outcome that optimizations with DFT B3LYP/6-31G(d) and MP2/6-311+G(d,p) model chemistries yield a resulting geometry which is in excellent agreement with the experimental findings. A DFT B3LYP/6-31G(d,p) computational investigation of the complexation process between β-cylodextrin and the amino acid alanine confirmed that β-CD can act as a chiral selector between the two enantiomeric forms of alanine. As a main result of the investigation of several neutral and anionic inclusion complexes of meloxicam with β-CD using DFT B3LYP/6-31G(d,p) calculations it was found that hydrogen bonding interactions are involved in the complexation process and support considerably the stabilization of the respective complexes. The results of all these investigations have been summarized in the following five papers: “Homodromic Hydrogen Bonds in Low-Energy Conformations of Single Molecule CDs”, “On the Structure of Anhydrous β-CD”, “Density Functional Calculations on CDs”, “Molecular Dynamics Simulations and Quantum Chemical Calculations on β-CD-Spironolactone Complex”, and “Density functional calculations on meloxicam-β-cyclodextrin Inclusion Complexes

Surface functionalized magnetic nanoparticles for separation of chiral biomolecules, pharmaceuticals and endocrine disrupting compounds

Ph.DDOCTOR OF PHILOSOPH

DFT study of the complexation of NOTA chelator with alkali metal and radiometal ions for radiopharmaceutical applications.

Master degree. University of KwaZulu-Natal, Westville. 2016The application of chelators is an ongoing interest in diagnostic and therapeutic radiopharmaceuticals. Bifunctional chelators labelled with radiometal ions are covalently bonded with a lead compound to form complexes with targeted biomolecules. The binding affinity of a ligand is thus an exclusively essential feature of an ideal radiopharmaceutical ligand. 1,4,7 triazacyclononane-1,4,7 triacetic acid (NOTA) a key radiolabelling chelator in radiopharmaceuticals, which is studied in this project, has been identified as one of the popularly investigated chelators. NOTA is known with the ability to form a stable complex with radiometal ions. A number of experimental investigations have been performed to study the structure and the radiolabelling efficiency of NOTA chelator while little attention has been paid to exploiting the structure and the binding features of the ligand at the molecular level. In this project, an investigation was made of the structure of NOTA and it complexation with alkali metal and radiometal ions, using density functional theory. In the first step, efforts were made to evaluate the complexation of NOTA with alkali metal ions (Na+ , Li+ , K+ and Rb+ ) with the intention of assessing the level of competition of alkali metal ions, found in the body. The complexation of NOTA with radiometal ions (Cu2+, Ga3+, In3+, Sc3+) was also investigated. This study reveals that nitrogen and oxygen atoms in the NOTA molecule are important for complexation processes. Interaction and relaxation energies, Gibbs free energies and entropies show that the stability of NOTA― alkali metal ion complexes decreases down the group of the periodic table. In the case of NOTA―radiometal ions complexes, NOTA― Ga3+ is identified to be more stable than the remaining radiometal complexes, which is in good agreement with experimentally reported binding constants. For both alkali metal and radiometal ion complexes, implicit water solvation affects the NOTA―ion complexation, causing a decrease in the stability of the system. NBO analysis performed through the natural population charges and second order perturbation theory reveals the charge transfer between NOTA and both alkali metal and radiometal ions. The theoretical 1H NMR chemical shifts of NOTA complexes, in vacuum and water, are in good agreement with experiment; these values are influenced by the presence of the ions, which have a deshielding effect on the protons of NOTA. A noteworthy conclusion from the investigation is that the interaction of NOTA with radiometal ions is stronger than the interaction of NOTA with alkali metal ions. Thus, confirming that the presence of alkali metal in human body may not interfere with the binding of radiometal to NOTA chelator. This study serves as a guide to researchers in the field of organometallic chelators, particularly, radio-pharmaceuticals in finding the efficient optimal match between chelators and different metal ions

Computational Approaches: Drug Discovery and Design in Medicinal Chemistry and Bioinformatics

This book is a collection of original research articles in the field of computer-aided drug design. It reports the use of current and validated computational approaches applied to drug discovery as well as the development of new computational tools to identify new and more potent drugs