Richard B. Silverman Patrick G. Ryan/Aon Professor of Chemistry, Molecular Biosciences

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

Design and Synthesis of Potent Quinazolines as Selective β-Glucocerebrosidase Modulators. Zheng J, Chen L, Schwake M, Silverman RB, and Krainc D. Journal of Medicinal Chemistry. 2016 September 22;59(18):8508-8520.

Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker. Wang H-Y, Qin Y, Li H, Roman LJ, Martásek P, Poulos TL, and Silverman RB. Journal of Medicinal Chemistry. 2016 May 26;59(10):4913-4925.

Tertiary Amine Pyrazolones and Their Salts as Inhibitors of Mutant Superoxide Dismutase 1-Dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis. Zhang Y, Zhao KT, Fox SG, Kim J, Kirsch DR, Ferrante RJ, Morimoto RI, and Silverman RB. Journal of Medicinal Chemistry. 2015 August 13;58(15):5942-5949.

Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase. Zigmond E, Ben Ya'acov A, Lee H, Lichtenstein Y, Shalev Z, Smith Y, Zolotarov L, Ziv E, Kalman R, Le HV, Lu H, Silverman RB, and Ilan Y. ACS Medicinal Chemistry Letters. 2015 August 13;6(8):840-844.

Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase by (1S,3S)-3-Amino-4-difluoromethylene-1-cyclopentanoic Acid (CPP-115). Lee H, Doud EH, Wu R, Sanishvili R, Juncosa JI, Liu D, Kelleher NL, and Silverman RB. Journal of the American Chemical Society. 2015 February 25;137(7):2628-2640.

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