Current Methods In Medicinal Chemistry And Biological Physics
- ISBN-10
- 8130801418
- ISBN-13
- 9788130801414
- Category
- Biophysics
- Pages
- 275
- Language
- English
- Published
- 2007-01-01
- Author
- Carlton A. Taft
Description
This book is aimed at, from students to advanced researchers, for anyone that is interested or works with current experimental and theoretical methods in medicinal chemistry and biological physics, with particular interest in chemoinformatics, bioinformatics, molecular modeling, QSAR, spectrometry, molecular biology and combinatorial chemistry for many therapeutic purposes. This book attempts to convey something of the fascination of working in these multidisciplinary areas, which overlap knowledge of chemistry, physics, biochemistry, biology and pharmacology. It contains 12 chapters, of which six are related to theoretical methods in Medicinal Chemistry, four deal with experimental methods and two discuss theoretical methods in Biological Physics. The role of the medicinal chemist has changed significantly in the past 25 years. From serendipity to rational drug design, much effort has been made in these two decades, with major participation of molecular modeling and QSAR. The insertion of computer-aided drug design technologies to the research and drug discovery approaches of a pharmaceutical company could lead to a reduction of up to 50% in the cost of drug design. In chapter 1, we present an overview of the state-of-the-art of computational methods currently used in medicinal chemistry, whereas in chapter 2, general aspects of lead finding and optimization are discussed. Quantitative Structure-Activity Relationships (QSAR) has a long history in the drug discovery field and reached a tremendous relevance in the optimization of promising leads. The impact of combinatorial library design and high throughput screening in drug design has created unique opportunities for the application of QSAR principles in information management, data analysis, and predictive model generation. In chapters 3 to 5, the main QSAR methods currently used are presented. Hologram QSAR (HQSAR) is a modern 2D QSAR technique that has proved its power and robustness in the creation of useful QSAR models to help medicinal chemists in their drug discovery projects in both academia and pharmaceutical industry, which is discussed in chapter 3. In chapter 4, some of the technologies that are needed to generate QSAR based on the three-dimensional description of the ligands, termed 3D QSAR, are discussed. The chapter considers mostly the models used when the 3D structure of the receptor is known. We do so because of the understanding that in the near future proteomics will identify all the therapeutically relevant targets and their 3D structures will be available. However, since this is not a necessary condition for developing a 3D QSAR model, we provide information regarding the description of the 3D structure of the small molecules required for developing a model. In chapter 5, the next-dimensions added to the 3D-QSAR methods include, beyond the third-dimension, multiple conformers as the fourth-dimension (4D), induced-fit as the fifth-dimension (5D), and solvent effect as the sixth-dimension (6D). An overview of these multidimensional-QSAR methods dealing with 4D, 5D, and 6D are discussed along with the approaches used to construct 3D-QSAR models using these additional dimensions such as the Receptor Independent (RI) and the Receptor Dependent (RD) 4D-QSAR and Quasar 4D/5D/6D-QSAR methods. The structure determination of an unknown organic compound is a very old challenge. To solve this problem in the past, chemists used different laboratorial approaches combined with spectrometric techniques. Since then, the amount of available data has considerable enhanced and nowadays this flood of information is still being accumulated while productivity is to some extent stagnated. With the fast development of the field of informatics combined with the availability of efficient algorithms there is a great expectation that computer programs can assist the researchers in structure elucidation. In the last years both academia and companies specialized in the development of chemical software decided to focus their research on this subject. In chapter 6, the main aspects of Computer-Assisted Structure Elucidation (CASE) are discussed, including artificial intelligence in its broad sense. In the two subsequent chapters, theoretical methods currently used in Biological Physics are presented. Chapter 7 discusses the protein-folding problem. The full understanding of the folding process, from any perspective, has proven to be a very difficult problem to be solved. Due to its importance for several branches of human activities, world wide efforts to describe in details the folding reaction have mobilized researchers and technicians from several scientific areas, projecting an optimistic vision for the near future with respect to the possibility of complete comprehension of the sequence-structure interdependence. However, as a grand challenge problem to be surmounted, different approaches have been employed in its treatment; here the minimalist model is emphasized. Humanity has always been afflicted by different type of plagues. Therefore, the search for scientific solutions, which can help to identify their causes and/or reduce their effects, has been made in several levels of the human organization through techniques and expertise of several areas of knowledge. A general (stochastic) formalism for the evolution of a population invaded by an infection is presented in chapter 8, in which the traditional Monte Carlo (MC) method is applied to the epidemics prediction. In chapters 9 to 12, current methods of interest for medicinal chemists are presented. In chapter 9, the basic concepts of mass spectrometry are introduced. The main part and aim of this chapter is to summarize the major ionisation techniques applied in modern laboratories for the analysis of organic molecules. No ionisation technique is universal, and each one has its own characteristic advantages and disadvantages. By careful use of this chapter, the authors hope that readers new to, or with limited experience of mass spectrometry, might learn about the uses and applications of each technique. Each section is accompanied with cartoon schematics of the ionisation sources and some ionisation mechanistic details. We have also provided references to major review articles in the literature that contain far more details on the developments of the techniques and the physical processes involved. In chapter 10, the use of zebrafish and mouse animal models as a current available tool and technology to fulfill drug discovery and development needs is explored. Those remarkable animal models play an important role as emerging tools to understand gene and molecule function and signaling pathways during disease and cancer initiation, development and progression. The RNA interference have been used to investigate the function of proteins that play a role in human diseases, to discover new regulators of pathways, and it has been considered as an alternative strategy for the treatment of many diseases. In chapter 11, we shortly discuss recent progress in its relevance as a research tool in molecular medicine and as a new therapy in the fight against cancer and others diseases. Finally, in chapter 12, we discuss the important role of combinatorial chemistry in drug discovery. Some contents of this book therefore reflect our own ideas and personal experiences, which are presented in reviews of different topics here investigated. It is interesting to consider the information described in this book as the starting point to access many available and varied knowledge in Medicinal Chemistry and Biological Physics or related areas.
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