Richard B. Silverman
John Evans Professor
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 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.
Substituted pyrazolones require N2 hydrogen bond donating ability to protect against cytotoxicity from protein aggregation of mutant superoxide dismutase 1. Trippier PC, Benmohammed R, Kirsch DR, and Silverman RB. Bioorganic & Medicinal Chemistry Letters. 2012 November 1;22(21):6647-6650.
Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase. Hawker DD and Silverman RB. Bioorganic & Medicinal Chemistry. 2012 October 1;20(19):5763-5773.
Antenatal insults modify newborn olfactory function by nitric oxide produced from neuronal nitric oxide synthase. Drobyshevsky A, Yu L, Yang Y, Khalid S, Luo K, Jiang R, Ji H, Derrick M, Kay L, Silverman RB, and Tan S. Experimental Neurology. 2012 October;237(2):427-434.
Selective Monocationic Inhibitors of Neuronal Nitric Oxide Synthase. Binding Mode Insights from Molecular Dynamics Simulations. Huang H, Ji H, Li H, JIng Q, Labby KJ, Martásek P, Roman LJ, Poulos TL, and Silverman RB. Journal of the American Chemical Society. 2012 July 18;134(28):11559-11572
Celastrol Analogues as Inducers of the Heat Shock Response. Design and Synthesis of Affinity Probes for the Identification of Protein Targets. Klaić L, Morimoto RI, and Silverman RB. ACS Chemical Biology. 2012 May;7(5):928-937.
3-(N-Arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2). Choi SH, Quinti L, Kazantsev AG, and Silverman RB. Bioorganic & Medicinal Chemistry Letters. 2012 April 15;22(8):2789-2793.
Intramolecular hydrogen bonding: A potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase. Labby KJ, Xue F, Kraus JM, Ji H, Mataka J, Li H, Martásek P, Roman LJ, Poulos TL, and Silverman RB. Bioorganic & Medicinal Chemistry. 2012 April 1;20(7):2435-2443.
Cyclohexane 1,3-diones and their inhibition of mutant SOD1-dependent protein aggregation and toxicity in PC12 cells. Zhang W, Benmohamed R, Arvanites AC, Morimoto RI, Ferrante RJ, Kirsch DR, and Silverman RB. Bioorganic & Medicinal Chemistry. 2012 January 15;20(2):1029-1045.
ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives To Block Mutant Superoxide Dismutase 1 (SOD1) Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis. Chen T, Benmohamed R, Kim J, Smith K, Amante D, Morimoto RI, Kirsch DR, Ferrante RJ, and Silverman RB. Journal of Medicinal Chemistry. 2012 January 12;55(1):515-527.
(1S, 3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction. Pan Y, Gerasimov MR, Kvist T, Wellendorph P, Madsen KK, Pera E, Lee H, Schousboe A, Chebib M, Bräuner-Osborne H, Craft CM, Brodie JD, Schiffer WK, Dewey SL, Miller SR, and Silverman RB. Journal of Medicinal Chemistry. 2012 January 12;55(1):357-366.
View all publications by Richard B. Silverman in the National Library of Medicine (PubMed).