Richard B. Silverman Professor
The research in my group can be summarized as investigations of the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents, particularly for neurodegenerative diseases. Numerous drugs are known to function as specific inhibitors of particular enzymes. When little is known about the enzyme’s molecular mechanism of action, chemical model studies are designed to determine reasonable nonenzymatic pathways applicable to the enzyme. Based on the proposed mechanism of enzyme action, inhibitors are designed and synthesized. Organic synthesis is a primary tool for this work. The enzymes are isolated from either mammalian tissue or from overexpressed cells containing recombinant enzymes. Active site labeling studies utilize MALDI TOF and electrospray ionization mass spectrometry as well as radiolabeled inactivators and peptide mapping. We also are synthesizing compounds to act as receptor antagonists for important receptors related to neurodegenerative diseases.
Holden, J. K.; Li, H.; Jing, Q.; Kang, S.; Richo, J.; Silverman, R. B.; Poulos, T. L. Structural and biological studies on bacterial nitric oxide synthase inhibitors. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 18127-18131.
Huang, H.; Li, H.; Yang, S.; Chreifi, G.; Martásek, P.; Roman, L. J.; Meyskens, F. L.; Poulos, T. L.; Silverman, R. B. Potent and Selective Double-headed Thiophene-2-carboximidamide Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma. J. Med. Chem. 2014, 57, 686-700.
Kang, S.; Cooper, G.; Dunne, S. F.; Dusel, B.; Luan, C.-H.; Surmeier, D. J.; Silverman, R. B. CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson’s disease. Nature Commun. 2012, 3, 1146.
Huang, H.; Ji, H.; Li, H.; Jing, Q.; Jansen Labby, K.; Martásek, P.; Roman, L. J.; Poulos, T. L; Silverman, R. B. Selective Monocationic Inhibitors of Neuronal Nitric Oxide Synthase. Binding Mode Insights from Molecular Dynamics Simulations. J. Am. Chem. Soc. 2012, 134, 11559-11572.
Klaić, L.; Morimoto, R. I.; Silverman, R. B. Celastrol Analogs as Inducers of the Heat Shock Response. Design and Synthesis of Affinity Probes for the Identification of Protein Targets. ACS Chem. Biol. 2012, 7, 928-937.
Silverman, R. B. The 2011 E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances: (1S,3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a GABA Aminotransferase Inactivator and New Treatment for Drug Addiction and Infantile Spasms. J. Med. Chem. 2012, 55, 567-575.
Chen, T.; Benmohamed, R.; Kim, J.; Smith, K.; Amante, D.; Morimoto, R. I.; Kirsch, D. R.; Ferrante, R. J.; Silverman, R. B. ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives to Block Mutant SOD1 Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis. J. Med. Chem. 2012, 55, 515-527.
Xue, F.; Li, H.; Delker, S.; Fang, J.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. Potent, Highly Selective, and Orally Bioavailable Gem-Difluorinated Monocationic Inhibitors of Neuronal Nitric Oxide Synthase, J. Am. Chem. Soc. 2010, 132(40), 14229-14238.
Silverman, R. B. Design of Selective Neuronal Nitric Oxide Synthase Inhibitors for the Prevention and Treatment of Neurodegenerative Diseases. Acc. Chem. Res. 2009, 42, 439-451.
Ji, H.; Tan, S.; Igarashi, J.; Li, H.; Derrick, M.; Martásek, P.; Roman, L. J.; Vásquez-Vivar, J.; Poulos, T. L.; Silverman, R. B. Selective Neuronal Nitric Oxide Synthase Inhibitors for Prevention of Cerebral Palsy, Ann. Neurol. 2009, 65, 209-217.
- 2014 Elected to American Academy of Arts & Sciences
- 2014 Excellence in Medicinal Chemistry Prize of the Israel Chemical Society
- 2013 Fellow of the Royal Society of Chemistry (UK)
- 2013 Centenary Prize of the Royal Society of Chemistry
- 2013 Bristol-Myers Squibb-Edward E. Smissman Award of the American Chemical Society (ACS)
- 2013 Roland T. Lakey Award from Wayne State University
- 2012 Sato Memorial International Award of the Pharmaceutical Society of Japan
- 2011 Fellow of the ACS
- 2011 E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances of the ACS
- 2011 Alumni Hall of Fame, Central High School of Central High School of Philadelphia
- 2009 Medicinal Chemistry Hall of Fame of the American Chemical Society
- 2009 Perkin Medal, Society of Chemical Industry
- 2008 Alumni Fellow Award, Pennsylvania State University
- 2003 Arthur C. Cope Senior Scholar Award of the American Chemical Society
- 2000 Northwestern University Alumni Association Excellence in Teaching Award
- 1999 E. LeRoy Hall Award for Teaching Excellence
- 1999 Excellence in Chemistry Education Award from the Northwestern University Chapter of Alpha Chi Sigma Chemistry Fraternity
- 1990 Fellow of the American Association for the Advancement of Science
- 1985 Fellow of the American Institute of Chemists
- 1982 NIH Research Career Development Awardee
- 1981 Alfred P. Sloan Research Fellow
- 1976 Du Pont Young Faculty Fellow