Richard B. Silverman Medicinal, bioorganic, and enzyme chemistry

Research Interests

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, lysosomal storage diseases, and cancer. 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 (computer modeling when applicable) and chemically synthesized. 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.

One enzyme inhibition project is related to γ-aminobutyric acid (GABA) aminotransferase. Compounds that inhibit this enzyme exhibit anticonvulsant activity and also are important in the treatment of addiction. We currently have a drug in clinical trials for epilepsy that inactivates this enzyme. A related enzyme we work with is ornithine aminotransferase; our inactivators slow the growth of hepatocellular carcinoma in mice. We also work with nitric oxide synthase, making selective inhibitors for the neuronal isozyme for the treatment of neurodegenerative diseases. We have also found that inhibitors of this enzyme slow the growth of melanoma and are synergistic with antibiotics. We have made activators of β-glucocerebrosidase for the potential treatment of Gaucher’s disease.  With the help of a high-throughput screen, we have developed compounds that stabilize corticospinal motor neurons in a mouse model of amyotrophic lateral sclerosis (ALS). My group does the organic synthesis, enzyme isolation, enzyme inhibition studies, and structure-based design. We collaborate with other groups for crystallography and animal studies.

Selected Publications

β-Glucocerebrosidase Modulators Promote Dimerization of β-Glucocerebrosidase and Reveal an Allosteric Binding Site. Zheng J, Chen L, Skinner OS, Ysselstein D, Remis J, Lansbury P, Skerlj R, Mrosek M, Heunisch U, Krapp S, Charrow J, Schwake M, Kelleher NL, Silverman RB, and Krainc D. Journal of the American Chemical Society. 2018 May 9;140(18):5914-5924.

Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions. Silverman RB. Chemical Reviews. 2018 April 11;118(7):4037-4070.

Design and Mechanism of (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction. Juncosa JI, Takaya K, Le HV, Moschitto MJ, Weerawarna PM, Mascarenhas R, Liu D, Dewey SL, and Silverman RB. Journal of the American Chemical Society. 2018 February 14;140(6):2151-2164.

Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker. Do HT, Wang H-Y, Li H, Chreifi G, Poulos TL, and Silverman RB. Journal of Medicinal Chemistry. 2017 November 22;60(22):9360-9375.

Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors. Cinelli MA, Li H, Chreifi G, Poulos TL, and Silverman RB. Journal of Medicinal Chemistry. 2017 May 11;60(9):3958-3978.

View all publications by Richard B. Silverman in the National Library of Medicine (PubMed).