Search Results

This chapter discusses macromolecular crystallography in drug discovery. Currently, all large and most small pharmaceutical and biotechnology companies have invested in macromolecular crystallography, with protein crystallography now an integral tool of drug discovery. During the last twenty years, the term rational drug design has slowly been replaced with the more precise term structure-based drug design (SBDD).

This chapter reviews the weak hydrogen bond in supramolecular chemistry by focusing on the relevance of these interactions in the analysis, design, and synthesis of the structures of molecular assemblies, most notably crystals. Supramolecular chemistry signifies chemistry beyond the molecule and deals with implications of the fact that molecules can recognise one another via intermolecular interactions, typically in condensed media. This field has grown into two distinct branches: the study of supermolecules in solution and in the solid state, mainly in crystal structures. The most important distinction between these two situations is not structural but lies in the lifetime of the interactions − supramolecular association in the crystal is time-stable whereas in solution it is not. The present chapter mainly concentrates on solid-state supramolecular systems, and discusses the role of weak hydrogen bonds in inclusion complexes such as crown ethers, oligoaryl hosts, and cyclodextrins (cycloamyloses). The promises and problems of crystal engineering are also considered, together with drug design and biological recognition.

This chapter explains how small molecules came to be used as drugs and how they function mechanistically. It begins by focusing on the emergence of organic chemistry and the role played by Justus von Liebig in the birth of organic chemistry through the isolation and synthesis of highly purified small molecules, paying special attention to his pioneering studies on fulminic acid and his collaboration with Friedrich Wohler that led to their discovery of the first example of isomers. The chapter then considers two related approaches for generating biologically active molecules: synthesis and extraction, along with Wohler’s synthesis of urea in 1828. It also discusses advances in extraction methods for purifying molecules from natural sources; the combination of extraction and synthesis methods to make derivatives of molecules found in nature, including the discovery of fever-reducing drugs; changes in the approach to drug discovery that laid the foundation for defining the problem of the undruggable proteins; the emergence of molecular medicine; and the rise of structure-based drug design.

Dr. Patricia Carter Sluby (Fig. 5.1) is a primary patent examiner retired from the US Patent and Trademark Office and formerly a registered patent agent. She is also the author of three books about African American inventors and their patented inventions. Patricia’s father is William A. Carter Jr., and her mother is Thelma LaRoche Carter. Her father was the first black licensed master plumber in Richmond, VA, and his father also had the same distinction in Columbus, OH, years earlier. Her father was born in Philadelphia, PA, and attended college. Her grandfather went from Virginia to look for work in Canada and became a stonemason. Later he relocated back to the United States, where he soon married in Boston, MA, and several of his children were born there. Later, the family moved to Philadelphia where Patricia’s father was born. Her mother, who attended Hampton Institute, taught school and later managed the office for Patricia’s father’s business. Patricia’s mother was born and raised in Richmond, as were most of her maternal relatives. Patricia had three brothers. They were all born during segregation in Richmond, the former capital of the Confederacy. Patricia was born on February 15, in Richmond. She attended kindergarten through eighth grade in segregated schools that were within walking distance of home. In school, they studied from hand-me-down books, but her black teachers were well trained and well informed. They had bachelor’s degrees; some had master’s or even PhD degrees. To go to high school, Patricia took a city bus across to the east side of town, to the newly built school for black students, which incorporated eighth grade through twelfth grade. Her teachers were excellent instructors who lived in her neighborhood and knew her parents quite well. The teachers looked out for the neighborhood kids and acted as surrogate parents out­side the confines of the home. Teachers and principals were also great mentors, dedicated to their craft; they encouraged students to understand the world and function as responsible adults. Patricia excelled in science and math.