DEPARTMENT OF CHEMISTRY

Affiliations

Patrick G. Ryan/Aon Professor

Department of Molecular Biosciences

Department of Pharmacology, Feinberg School of Medicine

Research Statement

The research in my group can be summarized as investigations of the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents. The primary focus is basic research into central nervous system disorders, including Parkinson’s disease, cerebral palsy, amyotrophic lateral sclerosis, addiction, and epilepsy. Other therapeutic areas include cancer (melanoma and hepatocellular carcinoma), lysosomal storage diseases, such as Gaucher’s disease, and bacterial infection. Numerous drugs are known to function as specific inhibitors of particular enzymes. For some enzyme targets, where potent reversible inhibitors are desired, computer modeling based on X-ray crystal structures initiates the research (high-throughput screening also may be used). For enzyme targets where inactivators are desired and 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. For those enzymes, mechanism-based inactivators are designed and synthesized and inactivation mechanisms investigated. The enzymes are isolated from either mammalian tissue or from overexpressed cells containing recombinant enzymes. Collaborations are developed in X-ray crystallography and preclinical studies.

Selected Publications

Zhu, W.; Doubleday, P. F.; Butrin, A.; Weerawarna, P. M.; Melani, R.; Catlin, D. S.; Dwight, T. A.; Liu, D.; Kelleher, N. L.; Silverman, R. B. Remarkable and unexpected mechanism for (S)-3-amino-4-(difluoromethylenyl)cyclohex-1-ene-carboxylic acid as a selective inactivator of human ornithine aminotransferase. J. Am. Chem. Soc. 2021, 143, 8193-8207.

Genç, B.; Gautam, M.; Gözütok, Ö.; Dervishi, I.; Sanchez, S.; Goshu, G. M.; Koçak, N.; Xie, E.; Silverman, R. B.; Özdinler, P. H. Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology. Clin. Transl. Med., 2021, 11, e336.

Shen, S.; Butrin, A.; Doubleday, P. F.; Melani, R. D.; Beaupre, B. A.; Tavares, M. T.; Ferreira, G. M.; Kelleher, N. L.; Moran, G. R.; Liu, D.; Silverman, R. B. Turnover and inactivation mechanisms for (S)-3-amino-4,4-difluorocyclopent-1-enecarboxylic acid, a selective mechanism-based inactivator of human ornithine aminotransferase. J. Am. Chem. Soc. 2021, 143, 8689-8703.

Zhu, W.; Doubleday, P. F.; Catlin, D. S.; Weerawarna, P. M.; Butrin, A.; Shen, S.; Wawrzak, Z.; Kelleher, N. L.; Liu, D.; Silverman, R. B. A remarkable difference that one fluorine atom confers on the mechanisms of inactivation of human ornithine aminotransferase by two cyclohexene analogues of -aminobutyric acid. J. Am. Chem. Soc. 2020, 142, 4892-4903.

Moschitto, M. J.; Doubleday, P. F.; Catlin, D. S.; Kelleher, N. L.; Liu, D.; Silverman, R. B. Mechanism of inactivation of ornithine aminotransferase by (1S,3S)-3-amino-4-(hexafluoropropan-2-ylidenyl)cyclopentane-1-carboxylic acid. J. Am. Chem. Soc. 2019, 141, 10711-10721.

Silverman, R. B. Design and mechanism of GABA aminotransferase inactivators, treatments for epilepsies and addictions. (invited) Chem. Rev. 2018, 118, 4037-4070.

Zheng, J.; Chen, L.; Skinner, O. S.; Remis, J.; Lansbury, P.; Skerlj, R.; Mrosek, M.; Heunisch, U.; Krapp, S.; Charrow, J.; Schwake, M.; Kelleher, N. L.; Silverman, R. B.; Krainc, D. -Glucocerebrosidase modulators promote dimerization of -glucocerebrosidase and reveal an allosteric binding site. J. Am. Chem. Soc. 2018, 140, 5914-5924.

Juncosa, J. I.; Takaya, K.; Le, H. V.; Moschitto, M. J.; Weerawarna, P. M.; Mascarenhas, R.; Liu, D.; Dewey, S. L.; Silverman, R. B. Design and mechanism of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, a highly potent GABA aminotransferase inactivator for the treatment of addiction. J. Am. Chem. Soc. 2018, 140, 2151-2164.

Holden, J. K.; Kang, S.; Beasley, F. C.; Cinelli, M. A.; Li, H.; Roy, S. G.; Dejam, D.; Edinger, A. L.; Nizet, V.; Silverman, R. B.; Poulos, T. L. Nitric oxide synthase as a target for methicillin resistant Staphylococcus aureus. Chem. Biol. 2015, 22, 785-792.

Zigmond, E.; Ya'acov, A. B.; Lee, H.; Lichtenstein, Y.; Shalev, Z.; Smith, Y.; Zolotarov, L.; Ziv, E.; Kalman, R.; Le, H. V.; Lu, H.; Silverman, R. B.; Ilan, Y. Suppression of hepatocellular carcinoma by inhibition of overexpressed ornithine aminotransferase. ACS Med. Chem. Lett. 2015, 6, 840-844.

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.

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.

Selected Honors/Awards

• 2021 Tetrahedron Prize for Creativity in Organic Chemistry
• 2017 Creative Invention Award of the American Chemical Society
• 2014 Fellow of the National Academy of Inventors
• 2014 Northwestern University Trustee Medal for Faculty Innovation and Entrepreneurship
• 2014 iCON Innovator Award (iBIO Institute)
• 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
• 2013 Roland T. Lakey Award from Wayne State University
• 2012 Sato Memorial International Award of the Pharmaceutical Society of Japan
• 2011 Fellow of the American Chemical Society
• 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
• 1990 Fellow of the American Association for the Advancement of Science