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

Patel, A.; Tong, S.; Lozada, K.; Awasthi, A.; Silverman, R. B.; Totonchy, J.; Yang, S. Targeting neuronal nitric oxide synthase (nNOS) as a novel approach to enhancing anti-melanoma activity of immune checkpoint inhibitors. Pharmaceutics 2025, 17(6), 691; https://doi.org/10.3390/pharmaceutics1706069. PMCID: PMC12196278

Patel, A.; Tong, S.; Roosan, M. R.; Syed, B.; Awasthi, A.; Silverman, R. B.; Yang, S. Crosstalk between nNOS/NO and COX-2 enhances interferon-gamma-stimulated melanoma progression. Cancers 2025, 17(3), 477. https://doi.org/10.3390/cancers17030477. PMCID: PMC11816268

Johnson, E. A.; Nowar, R.; Viola, K. L.; Huang, W.; Zhou, S.; Bicca, M. A.; Zhu, W.; Kranz, D. L.; Klein, W. L.; Silverman, R. B. Inhibition of amyloid beta oligomer accumulation by NU-9: a unifying mechanism for the treatment of neurodegenerative diseases. Proc. Natl. Acad. Sci. USA, 2025, 122(10), e2402117122. PMCID: PMC11912461

Wirt, J. L.; Assis Ferreira, L.; Jesus, C. H. A.; Woodward, T. J.; Oliva, I.; Xu, Z.; Crystal, J. D.; Pepin, R. H.; Silverman, R. B.; Hohmann, A. G. Efficacy of GABA aminotransferase inactivator OV329 in models of neuropathic and inflammatory pain without tolerance or addiction. Proc. Natl. Acad. Sci. USA 2025, 122(1), e2318833121; https://doi.org/10.1073/pnas.2318833121. PMCID: PMC11725897

Devitt, A. N.; Vargas, A. L.; Zhu, W.; Des Soye, B. J.; Butun, F. A.; Alt, T.; Kaley, N.; Ferreira, G. M.; Moran, G.; Kelleher, N. L.; Liu, D.; Silverman, R. B. Design, Synthesis, and Mechanistic Studies of (R)-3-Amino-5,5-difluorocyclohex-1-ene-1-carboxylic Acid as an Inactivator of Human Ornithine Aminotransferase. ACS Chem. Biol. 2024, 19(5), 1066-1081. PMCID: PMC11274680

Weerawarna, P. M.; Schiefer, I. T.; Soares, P.; Fox, S.; Morimoto, R. I.; Melani, R. D.; Kelleher, N. L.; Luan, C.-H.; Silverman, R. B. Target identification of a class of pyrazolone protein aggregation inhibitor therapeutics for amyotrophic lateral sclerosis. ACS Central Sci. 2024, 10(1), 87-103. DOI: 10.1021/acscentsci.3c00213. PMCID: PMC10823514

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. doi: 10.1021/acs.jmedchem.3c00782. PMCID: PMC10824152

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. PMCID: PMC8367020

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. PMCID: PMC7898037. doi:10.1002/ctm2.336

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 g-aminobutyric acid. J. Am. Chem. Soc. 2020, 142, 4892-4903. PMCID: PMC7134380

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