Drug Design and Relationship of Functional Groups to Pharmacologic Activity

Medicinal chemistry is an interdisciplinary science at the intersection of organic chemistry, biochemistry (bioorganic chemistry), computational chemistry, pharmacology, pharmacognosy, molecular biology, and physical chemistry. This branch of chemistry is involved with the identifi cation, design, synthesis, and development of new drugs that are safe and suitable for therapeutic use in humans and pets. It also includes the study of marketed drugs, their biologic properties, and their quantitative structure–activity relationships (QSARs). Medicinal chemistry studies how chemical structure infl uences biologic activity. As such, it is necessary to understand not only the mechanism by which a drug exerts its effect, but also how the molecular and physicochemical properties of the molecule infl uence the drug’s pharmacokinetics (absorption, distribution, metabolism, toxicity, and elimination) and pharmacodynamics (what the drug does to the body). The term “physicochemical properties” refers to how the functional groups present within a molecule infl uence its acid–base properties, water solubility, partition coeffi cient, crystal structure, stereochemistry, and ability to interact with biologic systems, such as enzyme active sites (Chapter 8) and receptor sites (Chapter 3). To design better medicinal agents, the relative contribution that each functional group (i.e., pharmacophore) makes to the overall physicochemical properties of the molecule must be evaluated. Studies of this type involve modifi cation of the molecule in a systematic fashion followed by a determination of how these changes affect biologic activity. Such studies are referred to as structure–activity relationships (SARs)—that is, the relationship of how structural features of the molecule contribute to, or take away from, the desired biologic activity. Because of the foundational nature of the content of this chapter, there are numerous case studies presented throughout the chapter (as boxes), as well as at the end. In addition, a list of study questions at the conclusion of—and unique to—this chapter provides further selfstudy material related to the subject of medicinal chemistry/drug design.