Richard Silverman


PhD, Harvard

Interdisciplinary Biological Sciences Program
Chemistry

Office Phone: 847.491.5653
Fax: 847.491.7713
Email
The Silverman Group

Research

The research in my group can be summarized as investigations of the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents. 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. On the basis of the proposed mechanism of enzyme action, inhibitors are designed and synthesized.  Organic synthesis is a primary tool for this work. 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 as well as radiolabeled inactivators and peptide mapping.

Two examples of enzymes of interest are nitric oxide synthase and GABA aminotransferase. Nitric oxide synthase, the enzyme that generates the important second messenger nitric oxide, exists in three isozymic forms, one in brain (nNOS), in macrophage (iNOS, the inducible form), and in endothelial cells (eNOS). Inhibitors of the brain isoform may be important in the treatment of a variety of neurodegenerative problems, but only if selective inhibition of this isoform can be accomplished to avoid blockage of NO production in cells where it is needed. We have synthesized several new classes of compounds that are highly selective for nNOS. We have many high resolution crystal structures (by collaboration) of the isozymes with some of our inhibitors bound and are using these structures for the design of new classes of inhibitors. Two of these compounds have been shown to be very effective in the prevention of cerebral palsy in a rabbit model. Another enzyme inhibition project is related to g‑aminobutyric acid (GABA) aminotransferase.  Compounds that inhibit this enzyme exhibit anticonvulsant and antiaddictive activity.  We are synthesizing compounds that can act as inactivators of this enzyme and are studying their mechanisms of inactivation.  One of our inactivators is currently in clinical trials.

My group does the organic synthesis, enzyme isolation, enzyme inhibition studies, structure-based design, and some pharmacokinetics studies. We collaborate with other groups for crystallography and animal studies.

 

Selected Publications

Kang, S.; Li, H.; Tang, W.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. 2-Aminopyridines with a truncated side chain to improve human neuronal nitric oxide synthase inhibitory potency and selectivity. J. Med. Chem. 2015, 58, 5548-5560.

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, 785-892.

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.

Tang, W.; Li, H.; Doud, E. H.; Chen, Y.; Choing, S.; Plaza, C.; Kelleher, N. L.; Poulos, T. L.; Silverman, R. B. Mechanism of inactivation of neuronal nitric oxide synthase by (S)-2-amino-5-(2-(methylthio)acetimidamido)pentanoic acid. J. Am. Chem. Soc. 2015, 137, 5980-5989.

Le, H. V.; Hawker, D. D.; Wu, R.; Doud, E.; Widom, J.; Sanishvili, R.; Liu, D.; Kelleher, N. L.; Silverman, R. B. Design and mechanism of tetrahydrothiophene-based GABA aminotransferase inactivators. J. Am. Chem. Soc. 2015, 137, 4525-4533.

Lee, H.; Doud, E. H.; Wu, R.; Sanishvili, R.; Juncosa, J. I.; Liu, D.; Kelleher, N. L.; Silverman, R. B. Mechanism of inactivation of g-aminobutyric acid aminotransferase by (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115). J. Am. Chem. Soc. 2015, 137, 2628-240.

Trippier, P. C.; Zhao, K. T.; Fox, S. G.; Schiefer, I. T.; Benmohamed, R.; Moran, J.; Kirsch, D. R.; Morimoto, R. I.; Silverman, R. B. Proteasome Activation is a Mechanism for Pyrazolone Small Molecules Displaying Therapeutic Potential in Amyotrophic Lateral Sclerosis. ACS Chem. Neurosci. 2014, 5, 823-829.

 

Links

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

Recent Photos

November 3, 2015