Research Statement
Our research involves studies of molecular mechanisms of action, rational design, and syntheses of potential medicinal agents that act as specific enzyme inhibitors. When little is known about the enzyme's molecular mechanism, enzymatic and chemical model studies are designed to determine reasonable pathways. Based on the proposed mechanism of enzyme action and/or on crystal structure data we obtain in collaboration, inhibitors are designed and synthesized and enzyme studies carried out.
Selected Publications
Clift, M.; Ji, H.; Deniau, G. P.; O’Hagan, D.; Silverman, R. B. The Enantiomers of 4-Amino-3-fluorobutanoic Acid as Substrates for g-Aminobutyric Acid Aminotransferase. Conformational Probes for GABA Binding. Biochemistry 2007, 46(48), 13819-13828.
Silverman, R. B. From Basic Science to Blockbuster Drug. The Discovery of Lyrica. Angew. Chem. Int. Ed. 2008, 47, 3500-3504.
Clift, M. D.; Silverman, R. B. Synthesis and Evaluation of Novel Aromatic Substrates and Competitive Inhibitors of GABA Aminotransferase. Bioorg. Med. Chem. Lett. 2008, 18 (10), 3122-3125.
Ji, H.; Stanton, B. Z.; Igarashi, J.;, Li, H.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. Minimal Pharmacophoric Elements and Fragment Hopping, an Approach Directed at Molecular Diversity and Isozyme Selectivity. Design of Selective Neuronal Nitric Oxide Synthase Inhibitors. J. Am. Chem. Soc. 2008, 130(12), 3900-3914.
Zhu, Y.; Silverman, R. B. Revisiting Heme Mechanisms. A Perspective on the Mechanisms of Nitric Oxide Synthase (NOS), Heme Oxygenase (HO), and Cytochrome P450s (CYP450s). Biochemistry 2008, 47(8), 2231-2243.
Trott, A.; West, J. D.; Klaic, L.; Westerheide, S. D.; Silverman, R. B.; Morimoto, R. I.; Morano, K. A. Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule. Mol. Biol. Cell 2008, 19(3), 1104-1112.
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.
Ji, H.; Erdal, E. P.; Litzinger, E. A.; Seo, J.; Zhu, Y.; Xue, F.; Fang, J.; Huang, J.; Silverman, R. B. Selective Neuronal Nitric Oxide Synthase Inhibitors. Frontiers in Medicinal Chemistry, Reitz, A. B.; Choudhary, M. I.; Atta-ur-Rahman, Editors; Bentham Science Publishers, Volume 5, 2009. in press.
Ji, H.; Li, H.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. Discovery of Highly Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase by Fragment Hopping. J. Med. Chem. 2009, 52 (3), 779–797.
Silverman, R. B. Design of Selective Neuronal Nitric Oxide Synthase Inhibitors for the Prevention and Treatment of Neurodegenerative Diseases. Acc. Chem. Res. In press.
Igarashi, J.; Li, H.; Jamal, J.; Ji, H.; Fang, J.; Lawton, G. R.; Silverman, R. B.; Poulos, T. L. Crystal Structures of Constitutive Nitric Oxide Synthases in Complex with De Novo Designed Inhibitors, J. Med. Chem. In press.
Lawton, G. R.; Ralay Ranaivo, H.; Wing, L. K.; Ji, H.; Xue, F.; Martásek, P.; Roman, L. J.; Watterson, D. M.; Silverman, R. B. Analogues of 2-aminopyridine-based selective inhibitors of neuronal nitric oxide synthase with increased bioavailability. Bioorg. Med. Chem. In press.
Most Significant Awards
2009 Perkin Medal, Society of Chemical Industry
2008 Alumni Fellow Award, Pennsylvania State University
1981 Alfred P. Sloan Research Fellow
1976 Du Pont Young Faculty Fellow
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
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