Preface

The areas of medicinal chemistry and drug design are constantly undergoing transformations. The molecular biological revolution and the mapping of the human genome have had a major impact, and these developments have provided new challenges and opportunities for drug research in general and for drug design in particular. The major objectives for medicinal chemists are the transformation of pathophysiological data into a "chemical language" with the aim of designing molecules interacting specifically with the derailed or degenerating processes in the diseased organism.

Potential therapeutic targets are continuously being disclosed, which calls for rapid and effective target validation and for accelerated lead discovery procedures. Consequently, industrial medicinal chemistry laboratories are regularly revising their technology portfolio to meet these demands. Key words in this regard are constructions of diverse compound libraries, fragment-based and high-throughput screening, as well as accelerated ADME and toxicity examinations.

In parallel with this development, biostructure-based drug design and intelligent molecular mimicry are indispensable areas of the medicinal chemistry playing field. Structural biology is playing an increasingly important role, and the borders between biology, biochemistry, and chemistry are broadening and becoming a most fruitful working field for innovative and intuitive scientists in drug design.

Academic medicinal chemistry and drug design departments need to attract the attention of bright students, interested in the creative and fascinating nature of drug design. In order to reach this goal it is of the utmost importance to maintain focus on the integration of the scientific disciplines of chemistry and biology. In relation to industrial "hit-finding" procedures, students should be taught that the conversions of hits into lead structures and further into drug candidates require the integration of a number of related scientific disciplines, such as advanced synthetic chemistry, computational chemistry, biochemistry, structural biology, and molecular pharmacology.

Advances in structural biology have opened up a number of exciting avenues in drug design. Three-dimensional structural information derived from x-ray analyses of enzyme-inhibitor complexes is applied for the design of new types of inhibitors. Similarly, structures of integral membrane proteins and cocrystal structures with ligands are emerging as important tools in receptor-ligand design. Such approaches are the foundation for drug design on a rational basis and are currently an important aspect of student teaching programs in medicinal chemistry.

The use of biologically active natural products has experienced a revival as a starting point for both industrial and academic drug design projects. Not only do natural products often possess novel structural characteristics, but they also frequently exhibit unique biological mechanisms of action, although naturally occurring toxins typically show nonselective pharmacological effects. Thus, by systematic structural modification such toxins can be converted into leads with specific biological functions of key importance in diseases.

This fourth edition of the textbook attempts to cover the diverse aspects of current academic and industrial medicinal chemistry and drug design in an educational context. The book is divided into two parts: Chapters 1 through 10 cover general aspects, methods, and principles for drug design and discovery, while Chapters 11 through 25 cover specific targets and diseases.

Povl Krogsgaard-Larsen Kristian Str0mgaard Ulf Madsen

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