Faculty
Richard Silverman, PhD
Professor
Chemistry
PhD., Harvard
Email: agman@chem.northwestern.edu
Phone: (847) 491-5653
Fax: (847) 491-7713
Room: Silverman Hall 4603
Research Interests
Bioorganic, medicinal, and enzyme chemistry: investigations of the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents, particularly for neurodegenerative diseases.
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. 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 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. We also are synthesizing compounds to act as receptor antagonists for important receptors related to neurodegenerative diseases.
One enzyme in which we are interested is nitric oxide synthase, the enzyme that generates the important second messenger nitric oxide. This enzyme 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, such as Parkinson’s disease, Alzheimer’s disease, cerebral palsy, and stroke, 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. In collaboration with a crystallographer at UC Irvine, we have many high resolution crystal structures (see the figure for one of our inhibitors bound to nNOS) of all 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 γ aminobutyric acid (GABA) aminotransferase. Compounds that inhibit this enzyme exhibit anticonvulsant activity and are important in the treatment of addiction. We are synthesizing compounds that can act as inactivators of this enzyme and are studying their mechanisms of inactivation.
The group also has receptor antagonism projects in collaboration with groups at our medical school as well as at other universities dealing with potential treatments for Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s disease. We have run high throughput screens (HTS) at the Northwestern HTS facility and have collaborated with other groups running HTS in search of lead compounds for these diseases. For the ALS project we have modified the lead to make potent compounds, have studied microsomal and plasma stability of the compounds, have modified the compounds to avoid the metabolic problems, and produced compounds being studied (in collaboration) in an animal model for 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
Effect of potential amine prodrugs of selective neuronal nitric oxide synthase inhibitors on blood-brain barrier penetration. Silverman RB, Lawton GR, Ralay Ranaivo H, Chico LK, Seo J, Watterson DM. Bioorg Med Chem. 2009 Nov 1;17(21):7593-605. Epub 2009 Sep 6.
Synthesis and enzymatic evaluation of 2- and 4-aminothiazole-based inhibitors of neuronal nitric oxide synthase. Lawton GR, Ji H, Martásek P, Roman LJ, Silverman RB. Beilstein J Org Chem. 2009 Jun 4;5:28.
L337H mutant of rat neuronal nitric oxide synthase resembles human neuronal nitric oxide synthase toward inhibitors. Fang J, Ji H, Lawton GR, Xue F, Roman LJ, Silverman RB. J Med Chem. 2009 Jul 23;52(14):4533-7.
A cellular model for screening neuronal nitric oxide synthase inhibitors. Fang J, Silverman RB. Anal Biochem. 2009 Jul 1;390(1):74-8. Epub 2009 Apr 9.
Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy. Ji H, Tan S, Igarashi J, Li H, Derrick M, Martásek P, Roman LJ, Vásquez-Vivar J, Poulos TL, Silverman RB. Ann Neurol. 2009 Feb;65(2):209-17.
Design of selective neuronal nitric oxide synthase inhibitors for the prevention and treatment of neurodegenerative diseases. Silverman RB. Acc Chem Res. 2009 Mar 17;42(3):439-51.
From basic science to blockbuster drug: the discovery of Lyrica. Silverman RB. Angew Chem Int Ed Engl. 2008;47(19):3500-4. No abstract available.
View all publications by Richard B. Silverman in the National Library of Medicine (PubMed). Past and current IBiS students in blue