This book is aimed at, from students to advanced researchers, for anyone that is interested or works with medicinal chemistry, at experimental or theoretical levels for many therapeutic purposes. We attempt to convey a few selected topics stimulating the fascination of working in these multidisciplinary areas, which overlaps knowledge of chemistry, physics, biochemistry, biology and pharmacology. This book contains 7 chapters, of which 3 are related to theoretical methods in medicinal chemistry whereas the others deal with experimental/mixed methods.
In modern computational medicinal chemistry, quantum mechanics (QM) plays an important role since the associated methods can describe molecular energies, bond breaking or forming, charge transfer and polarization effects. Historically in drug design, QM ligand-based applications were devoted to investigations of electronic features, and they have also been routinely used in the development of quantum descriptors in quantitative structure-activity relationships (QSAR) approaches. Today, QM-based methods are crucial in ligand-protein binding which is the essence of drug discovery and design. In chapter 1, we present an overview of the state-of-the-art of QM-based methods currently used in medicinal chemistry. Bioisosterism, quantum chemical topology, free energy simulations, solvation thermodynamics, docking and scoring, weak interactions as well as selected applications to various diseases are discussed.
Glycogen Synthase Kinase-3β (GSK-3β), a serine/threonine kinase, has emerged as one of the most attractive therapeutic targets for the treatment of the Alzheimer's disease (AD). This enzyme has been linked to all the primary abnormalities associated with AD, including hyperphosphorylation of the microtubule-associated protein tau, which contribute to the formation of neurofibrillary tangles, and its interactions with others Alzheimer's disease-associated proteins. Thus, the significant role of GSK-3β in essential events in the pathogenesis of AD makes this kinase an attractive therapeutic target for neurological disorders. Chapter 2 explores the nature and the structure of this promising enzyme, focusing on the structure-based design of new GSK-3β inhibitors.
Computational chemistry can be used to predict physicochemical properties, energies, binding modes, interactions and a large amount of helpful data in lead discovery and optimization. Interactions between a ligand and a molecular target structure can be investigated using molecular interaction fields (MIF). Employing such approaches, it is possible to identify regions where specific chemical groups of a ligand molecule can interact favorably with another target molecule, suggesting pharmacore models or virtual receptor sites. In chapter 3, we discuss how molecular interaction fields have been extensively used in drug discovery projects including a variety of applications: 3D-QSAR, virtual screening, similarity of protein targets and specificity of ligands, prediction of pharmacokinetic properties and determination of ligand binding sites in biomolecular target structures.
The development of quantitative structure-activity relationships (QSARs or 2D-QSARs) is a science that has developed without a defined framework, series of rules, or guidelines for methodology. It has been more than 40 years since the QSAR paradigm first found its way into the practice of agrochemistry, pharmaceutical chemistry, toxicology, and eventually most facets of chemistry. Its staying power may be attributed to the strength of its initial postulate that activity is a function of structure as described by electronic attributes, hydrophobicity, and steric properties as well as rapid and extensive development in methodologies and computational techniques that have ensued to delineate and refine the many variables and approaches that define the paradigm. The overall goals of QSAR retain their original essence and remain focused on the predictive ability of the approach and its receptiveness to mechanistic or diagnostic interpretations. Our intention with chapter 4 is to offer the basis of the QSAR approach in a clear and intuitive way, with maximum simplification and trying to close the gap that exists between maths and students of pharmacy. Moreover, the interpretation of the equations is even more important than statistically obtaining significant and robust relationships. We will show our results on Choline Kinase (ChoK) inhibitors as antiproliferative agents to demonstrate the possibilities of the Hansch model in the drug design process.
The issue of drug chirality is now a major theme in the design and development of new drugs, and our aim in chapter 5 is to discuss its importance in Medicinal Chemistry, underpinned by a new understanding of the role of molecular recognition in many pharmacologically relevant events. In general, three methods are utilized for the production of a chiral drug: the chiral pool, separation of racemates, and asymmetric synthesis. Although the use of chiral drugs predates modern medicine, only since the 1980's has there been a significant increase in the development of chiral pharmaceutical drugs. The thalidomide tragedy increased awareness of stereochemistry in the action of drugs, and as a result the number of drugs administered as racemic compounds has steadily decreased. In 2001, more than 70% of the new chiral drugs approved were single enantiomers. Approximately 1 in 4 therapeutic agents are marked as racemic mixtures, the individual enantiomers of which frequently differ in both their pharmacodynamic and pharmacokinetic profiles. The use of racemates has become the subject of considerable discussion in recent years, and an area of concern for both the pharmaceutical industry and regulatory authorities. Pharmaceutical companies are required to justify each decision to manufacture a racemic drug in preference to its homochiral version. Moreover, the use of single enantiomers has a number of potential clinical advantages, including an improved therapeutic/pharmacological profile, a reduction in complex drug interactions, and simplified pharmacokinetics. In a number of instances stereochemical considerations have contributed to an understanding of the pharmacological effects observed for a drug administered as a racemate. However, relatively little is known of the influence of patient factors (e.g. disease state, age, gender and genetics) on drug enantiomer disposition and action in man. Examples may also be cited where the use of a single enantiomer, non-racemic mixtures and racemates of currently used agents may offer clinical advantages. The issues associated with drug chirality are complex and depend upon the relative merits of the individual agent. In the future it is likely that a number of existing racemates will be re-marketed as single enantiomer products with potentially improved clinical profiles and possible novel therapeutic indications.
Microwaves are a powerful and reliable energy source that may be adapted to many applications. Since the introduction of microwave-assisted organic synthesis in 1986, the use of microwave irradiation has now introduced a completely new approach to drug discovery. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times has recently fascinated many pharmaceutical companies, which are incorporating microwave chemistry into their drug development efforts. Thus, the time saved by using focused microwaves is important either in traditional organic synthesis or in high-speed medicinal chemistry, which has been analyzed by us in chapter 6.
The high abundance of carbohydrates in nature and their diverse roles in biological systems validate the increasing interest for their chemical and biological research. Carbohydrates can be found as monomers or oligomers, or as glycoconjugates, which are formed by an oligosaccharide moiety joined to a protein (glycoproteins) or to a lipid moiety (glycolipids). Blood groups determinants (ABH), tumor associated antigens and pathogen binding sites are some of the relevant glycoconjugates found in mammalian cells. It is well known that carbohydrate and glycoconjugate molecules are implicated in many cellular processes, especially in biological recognition events, including cell adhesion, differentiation and growth, signal transduction, protozoa, bacterial and virus infection, and immune response. Therefore, the demand for glycans and glycoconjugates for various studies of targets involved in several serious diseases have been continuously growing. In chapter 7 we discuss the design of drugs based on carbohydrate structure for treatment of parasitic diseases (T. cruzi) and virus infections (influenza and HIV). Moreover, the development of glycoconjugate antitumor vaccines related to the structure of human mucin-associated glycans will also be outlined.
Some contents of this book also reflect some of our own ideas and personal experiences, which are presented in selected topics. It is interesting to consider the information described in this book as the starting point to access considerable available and varied knowledge in the Medicinal chemistry field.
Carlton A. Taft
Brazilian Center for Physics Research,
Rio de Janeiro,