DEPARTMENT OF CHEMISTRY

Affiliations

Patrick G. Ryan/Aon Professor

Department of Molecular Biosciences

Department of Pharmacology, Feinberg School of Medicine

Chemistry of Life Processes Institute

Research Statement

The research in my group can be summarized as investigations of the rational design, syntheses, and molecular mechanisms of action of potential medicinal agents. The primary focus is basic research into central nervous system disorders, including amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, cerebral palsy, epilepsy, and neuropathic pain. Other therapeutic areas include cancer (melanoma and hepatocellular carcinoma). 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, mechanism-based inactivators are designed and synthesized and inactivation and metabolism mechanisms investigated. The enzymes are isolated from overexpressed cells containing recombinant enzymes. Collaborations are developed in X-ray crystallography and preclinical studies. We have invented several drugs, one of which (Lyrica) is on the drug market and three others have been or are in clinical trials.

Selected Publications

Vasu, D.; Do, H. T.; Li, H.; Hardy, C. D.; Poulos, T. L.; Silverman, R. B. Potent, selective, and membrane permeable 2-amino-4-substituted pyridine-based neuronal nitric oxide synthase inhibitors. J. Med. Chem. 2023, 66, 9934-9953.

Zhu, W.; Butrin, A.; Melani, R. D.; Doubleday, P. F.; Ferreira, G. M.; Tavares, M. T.; Habeeb Mohammad, T. S.; Beaupre, B. A.; Kelleher, N. L.; Moran, G. R.; Liu, D.; Silverman, R. B. Rational design, synthesis, and mechanism of (3S,4R)-3-amino-4-(difluoromethyl)cyclopent-1-ene-1-carboxylic acid: employing a second deprotonation strategy for selectivity of hOAT over GABA-AT. J. Am. Chem. Soc., 2022, 144, 5629-5642.

Genç, B.; Gautam, M.; Helmold, B.; Koçak, N.; Günay, A.; Goshu, G. M.; Silverman, R. B.; Özdinler P. H. NU-9 improves health of hSOD1G93A mouse upper motor neurons in vitro, especially in combination with riluzole or edaravone. Sci. Rep. 2022, 12, 5383.

Tong, S.; Cinelli, M.; Ibrahim, N.; Huang, H.; Silverman, R. B.; Yang, S. Inhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS). Scientific Reports, 2022, 12, 1701.

Silverman, R. B. Inactivators of ornithine aminotransferase for the treatment of hepatocellular carcinoma. ACS Med. Chem. Lett. 2022, 13, 38-49.

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.

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.

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.

Cooper, G.; Kang, S.; Perez-Rosello, T.; Guzman, J. N.; Galtieri, D.; Xie, Z.; Kondapalli, J.; Mordell, J.; Silverman, R. B.; Surmeier, D. J. A single amino acid determines the selectivity and efficacy of selective negative allosteric modulators of CaV1.3 L-type calcium channels. ACS Chem. Biol. 2020, 15, 2539-2550.

Cinelli, M. A.; Reidl, C. T.; Li, H.; Chreifi, G.; Poulos, T. L.; Silverman, R. B. First contact: 7-Phenyl-2-aminoquinolines, potent and selective neuronal nitric oxide synthase inhibitors that target an isoform-specific aspartate. J. Med. Chem.2020, 63 (9), 4528–4554.

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.

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.

Selected Honors/Awards

• 2024 Esselen Award for Chemistry in the Public Interest of the American Chemical Society
• 2024 Abeles and Jencks Award for the Chemistry of Biological Processes of the American Chemical Society
• 2023 National Academy of Sciences, Member
• 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