Quantitative In Silico Chromatography

• Preface;Introduction;Basic Concept of Moelcuar Interaction Energy Values;Design Model-Phases in Chromatography;Retention in Gas Chromatography;Retention in Normal-Phase Liquid Chromatography;Retention in Reversed-Phase Liquid Chromatography;Retention in Ion-Exchange Liquid Chromatography;Enantiomer Recognition;Human Serum Albumin-Drug Binding Affinity Based on Liquid Chromatography;Affinity and Reactivity of Proteins;Mechanism of Highly Sensitive Detection;Appendix;Subject Index

All early chromatographic techniques, starting from the primitive “ancient” chromatography introduced by Tswett in the very early twenties century, perfected in partition chromatography in the 1940s by Martin and Synge, and extended to a variety of additional separation mechanisms later, were first entirely experimental trial-and-error methods. The early years can also be characterized by searching for theoretical base of various separation techniques that would allow establishing relation between the structure of the analytes and their chromatographic behavior. The advent of computers followed by development of the new software then revolutionized the theoretical approaches and enabled detailed modelling instead of tedious experimentation. This book introduces the readers in the era of computational modelling in which the molecular interactions are used to analyze the mechanisms of general molecular interactions with a special focus on biological applications.The book has 11 chapters each subdivided in several sections. The first chapter, Introduction, briefly summarizes the contents of the book and represents kind of scientific curriculum vitae of the author himself since all references except for one are to his own papers. It speaks about fundamental phenomena in chromatography, briefly describes use of liquid chromatography for description of binding affinity between human serum albumin and drugs, shows basics of proteins in affinity stationary phases, and ends with mechanisms of highly selective detection.Rather short chapter 2 deals with energies of different molecular interactions with an accent on those that are felt as most important for successful separations using various liquid chromatography mechanisms. In fact, Figure 1.1 in the previous chapter summarizes all these methods and shows what types of interactions affect them most. Out of 12 interactions shown in the Figure 1.1, chapter 2 details four: hydrophobic van der Waals interactions, hydrogen bonding, ion-ion or Coulombic forces, and steric hindrance mostly effective in enantioseparations.Chapter 3 describes modelling of two stationary phases, graphitized carbon and silica gels. The former is approached as multilayer system of polycyclic aromatic hydrocarbon2coronene. Interactions of aliphatic and aromatic hydrocarbons, and alcohols with those phases are also shown. The latter phase, silica, is constructed by computer-assisted polymerization to form a three-dimensional object, which silanol groups are then bonded with silanes and endcapped. The modelling enables to view the three-dimensional structures of the stationary phases.Next chapter emphasizes calculation of retention in gas chromatography. It handles several typical GC phases including graphitized carbon described in previous chapter, methylsilicone, methylphenylsilicone, and poly(ethylene glycol). This chapter concludes with a Table summarizing interactions affecting the GC separations using selected phases.Chapters 5 and 6 introduce calculations of interaction energies related to retention in normal phase and reversed phase liquid chromatography. Once again, two stationary phases, graphitized carbon and silica gels, are used for the modelling of both techniques. The normal phase part deals with saccharides and aromatic molecules used as analytes. The author also describes the effect of acidic and basic components of the entirely organic mobile phase on interaction of simple molecules and selected drugs, and shows the effect of molecular interaction energy on retention factors.Reversed phase separation is the most often applied technique in liquid chromatography. This is why Chapter 6 is with its 61 pages is the longest in the book. In contrast to normal phase, reversed phase separations are carried out in aqueous mobile phases containing organic modifier. Calculations confirmed experimental findings demonstrating that retention depends on the alkyl chain length of the silica based bonded phases. These phases are well known to be the workhorse of the reversed phase liquid chromatography. Brief attention is devoted to graphitized carbon that is much less common in reversed phase separations. Several sections are devoted to modeling selectivity and separations of individual groups of analytes such as phenolic compounds, benzoic acid derivatives, aromatic acids, and both acidic and basic drugs. The chapter ends with description of effect of the organic solvents used as a modifier in the mobile phase.Following Chapter 7 reflects author’s studies related to ion exchange chromatography with treating both cation and anion exchange separately. Compared to normal phase and reversed phase, this chromatographic mode depends on different sets of interactions that are mostly electrostatic. Specifically, in silico quantitative analysis of interaction energy and retention factors for basic drugs and acidic compounds is presented with emphasis on the effects of pKa.I found Chapter 8 interesting since it handles enantioseparations, where the separations of compounds, which are identical in non-chiral environment, are achieved due to the difference in free energy of interaction of individual enantiomers with the chiral selector. The chapter starts with introduction of several “brush-type” chiral separation phases and in several tables presents the energy values and molecular properties of individual amino acid enantiomers and the calculated selectivity factors. A short section introduces3recognition via ligand exchange that has been first introduced by Davankov in 1971. It is a pity that this early work is not cited. Much more space is given to reversed phase separations of diastereomers and enantioseparations using cyclodextrin-based phases.The last three chapters concern topics that are less related to separation mechanisms. Chapter 9 covers binding of drugs to human serum albumin, which is the most common transport protein in the blood. These interactions and their calculations are important in design and high throughput screening of new drug candidates. Chromatography is an almost perfect method to confirm the affinity that has been first predicted in silico. This chapter also features most references with 80 of them. Following chapter looks at affinity of proteins to certain compounds. The presented approach enable modelling of so called “docking”, i.e. calculations of structures protein-specific small molecule. Selectivity and conformational analysis of monoamine oxidase and D-amino acid oxidase are treated in more detail. The last chapter then relates to highly sensitive detection where the calculations certainly help but the direct relation to chromatography mechanisms is somewhat blurred. This part focuses on reaction mechanisms instead, exemplified them with bromate and chemiluminescent detection.Quite extensive Appendix collects 18 large tables that relate to topics presented in the individual chapters. For example, these tables are showing for a number of compounds molecular properties and interaction energies, retention times as a function of interaction energies, calculated atomic partial charge data, predicted and measured pKa values, molecular properties of phenolic compounds, predicted and measured retention factors, molecular properties and interaction energies of benzoic acid derivatives. I find these tables very valuable source of condense information that might be difficult to find elsewhere. The book is then completed with a 12 pages long subject index.The overall quality of the book is really good. I found surprisingly little typos (e.g. page 27 SO2 instead of SiO2) and misspellings (names are incorrect in reference to the famous work of Nobel Prize winner Anfinsen in chapters 1 and 10). Since this book mostly presents lifelong achievements of the author, it is not a comprehensive review of the entire field. However, reading this book can be very useful for novices in the in silico chromatography and for those who do not want to tiresomely dig through the original papers. It can also be a good springboard for scientists and engineers alike in need of rapid access to data that are typically buried in the publications and difficult to find using the current search engines