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Richard B. Silverman, Ph.D.

Richard B. Silverman is the John Evans Professor of Chemistry at Northwestern University. Professor Silverman received his B.S. degree in chemistry from The Pennsylvania State University in 1968 and his Ph.D. degree in organic chemistry from Harvard University (David H. Dolphin, mentor) in 1974 with time off for a two-year military obligation from 1969-1971. After two years as a NIH postdoctoral fellow in the laboratory of the late Professor Robert H. Abeles in the Graduate Department of Biochemistry at Brandeis University, he joined the chemistry faculty at Northwestern University. In 1986 he became Professor of Chemistry and Professor of Biochemistry, Molecular Biology, and Cell Biology. In 1996 he was named the Arthur Andersen Professor of Chemistry for a period of two years and since 2004 he has been the John Evans Professor of Chemistry. He has supervised 125 graduate students and postdoctoral associates at Northwestern.

Professor Silverman’s research can be summarized as investigations of enzyme mechanisms and the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents, particularly for central nervous system diseases. Dr. Silverman has formulated and tested new enzymatic hypotheses with the use of novel organic chemical approaches to elucidate enzyme-catalyzed reactions, to design mechanism-based inactivators of enzymes, and to understand the molecular mechanisms of inactivation of enzymes. The enzymes that he studies are not only mechanistically interesting, but also highly relevant to pharmaceutical inhibitor design. For example, with the use of a variety of novel mechanism-based inactivators, Dr. Silverman pioneered and developed the mechanistic work that led to a radical mechanism for the enzyme monoamine oxidase. When he first reported his results in 1980, radical involvement in enzyme-catalyzed reactions was rarely proposed and poorly understood. It is now apparent that radical intermediates in enzyme-catalyzed reactions are quite prevalent.

Detailed mechanisms of inactivation of γ-aminobutyric acid (GABA) aminotransferase, the enzyme that degrades the inhibitory neurotransmitter GABA, were elucidated by Dr. Silverman. Compounds that inhibit this enzyme raise the brain levels of GABA, which has an anticonvulsant effect. Over the years he has demonstrated that few inactivators proceed by a single inactivation mechanism. For example, he showed that the antiepilepsy drug, vigabatrin (Sabril™), inactivates GABA aminotransferase by three different pathways.

For a compound to act as a drug that inhibits GABA aminotransferase, it is imperative that it does not also inhibit the enzyme responsible for the production of GABA, namely glutamate decarboxylase; otherwise, this would defeat the purpose of inhibiting its degradation. The other important feature of a potential CNS drug is its ability to enter the brain. A series of compounds was designed by Professor Silverman to inhibit GABA aminotransferase without inhibition of glutamate decarboxylase and to have increased lipophilicity for brain penetration. Unexpectedly, these compounds activated glutamate decarboxylase and produced additional GABA. These compounds were tested for anticonvulsant activity because of this potential new mechanism to increase brain GABA levels, and one of them, after an additional 14 years of testing in animals and in humans, became Lyrica™ (pregabalin), the first FDA-approved treatment for diabetic neuropathy, postherpetic neuralgia, and fibromyalgia; it is also effective in the treatment of epilepsy.

Other early enzyme studies in Professor Silverman’s lab include model studies for the mechanism of vitamin K epoxide reductase and orotidine 5’-phosphate decarboxylase and investigations of the mechanism and inactivation of nitric oxide synthase (NOS), an enzyme important for regulation of the blood pressure, the immune defense system, and brain development and memory. Excess production of nitric oxide, however, is implicated in numerous neurodegenerative diseases. Professor Silverman designed the first dual-selective inhibitors of the neuronal isozyme of NOS and used these in collaboration with the crystallography group of Thomas Poulos at the University of California, Irvine to obtain crystal structures of these potent and selective reversible inhibitors. The obtained structures were employed to develop a new fragment-based de novo design of a class of more potent and selective compounds that have been found to be remarkably active in a rabbit model for cerebral palsy.

Professor Silverman has received numerous awards for research: DuPont Young Faculty Fellow (1976), Alfred P. Sloan Research Fellow (1981-1985), NIH Research Career Development Awardee (1982-1987), Fellow of the American Institute of Chemists (1985), Fellow of the American Association for the Advancement of Science (1990), Arthur C. Cope Senior Scholar Award of the American Chemical Society (2003), Alumni Fellow Award from The Pennsylvania State University (2008), and the Perkin Medal from the Society of Chemical Industry (2009). He also is the recipient of several teaching awards including the E. LeRoy Hall Award for Teaching Excellence (1999), the Excellence in Chemistry Education Award from the Northwestern University Chapter of Alpha Chi Sigma Chemistry Fraternity (1999), the Northwestern University Alumni Teaching Award (2000), and the Charles Deering McCormick Chair in Teaching Excellence (2001). Professor Silverman also was awarded a U.S. Army Commendation Medal for meritorious service (1971).

Editorial Advisory Boards on which Professor Silverman has served include the following journals: Current Enzyme Inhibition (2004-present), Bioorganic & Medicinal Chemistry (2003-present), Bioorganic & Medicinal Chemistry Letters (2003-present), Letters in Drug Design & Discovery (2003-present), Archiv der Pharmazie- Pharmaceutical and Medicinal Chemistry (1995-present), Journal of Enzyme Inhibition and Medicinal Chemistry (1988-present), Archives of Biochemistry and Biophysics (1993-2003), and Journal of Medicinal Chemistry (1995-2000).

Dr. Silverman has published over 250 research articles and reviews, holds 41 domestic and foreign patents, and has written four books (one translated into German). His book entitled “The Organic Chemistry of Drug Design and Drug Action” is in its second edition. From 1992-2006 he gave two-day short courses on drug design and drug action at the national meetings of the American Chemical Society, as well as at various pharmaceutical companies. He has been a lecturer at the Residential School on Medicinal Chemistry (Drew University) since 1995, presenting lectures on enzyme inhibition and on lead modification. He was elected nominating committee (1990), treasurer (1993-1996), and program chair (2001) of the Division of Biological Chemistry of the American Chemical Society and canvassing committee (1982-1987; chair 1987) and long-range planning committee, Division of Medicinal Chemistry of the American Chemical Society.

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