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.
Microwave-Assisted Protection of Primary Amines as 2,5-Dimethylpyrroles and Their Orthogonal Deprotection. Walia A, Kang S, and Silverman RB. Journal of Organic Chemistry. 2013 November 1;78(21):10931-10937.
Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors. Jing Q, Li H, Chreifi G, Roman LJ, Martásek P, Poulos TL, and Silverman RB. Bioorganic & Medicinal Chemistry Letters. 2013 October 15;23(20):5674-5679.
Two continuous coupled assays for ornithine-δ-aminotransferase. Juncosa JI, Lee H, and Silverman RB. Analytical Biochemistry. 2013 September 15;440(2):145-149.
In search of potent and selective inhibitors of neuronal nitric oxide synthase with more simple structures. Jing Q, Li H, Fang J, Roman LJ, Martásek P, Poulos TL, and Silverman RB. Bioorganic & Medicinal Chemistry. 2013 September 1;21(17):5323-5331.
Antagonism of L-type Ca2+ channels CaV1.3 and CaV1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics. Kang S, Cooper G, Dunne SF, Luan C-H, Surmeier DJ, and Silverman RB. Bioorganic & Medicinal Chemistry. 2013 July 15;21(14):4365-4373.
Methylated Nω-Hydroxy-L-arginine Analogues as Mechanistic Probes for the Second Step of the Nitric Oxide Synthase-Catalyzed Reaction. Jansen Labby K, Li H, Roman LJ, Martásek P, Poulos TL, and Silverman RB. Biochemistry. 2013 May 7;52(18):3062-3073.
Structure-Guided Design of Selective Inhibitors of Neuronal Nitric Oxide Synthase. Huang H, Li H, Martásek P, Roman LJ, Poulos TL, and Silverman RB. Journal of Medicinal Chemistry. 2013 April 11;56(7):3024-3032.
Arylazanylpyrazolone Derivatives as Inhibitors of Mutant Superoxide Dismutase 1 Dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis. Zhang Y, Benmohamed R, Huang H, Chen T, Voisine C, Morimoto RI, Kirsch DR, and Silverman RB. Journal of Medicinal Chemistry. 2013 March 28;56(6):2665-2675.
Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase. Li H, Xue F, Kraus JM, Ji H, Jansen Labby K, Mataka J, Delker SL, Martásek P, Roman LJ, Poulos TL, and Silverman RB. Bioorganic & Medicinal Chemistry. 2013 March 1;21(5):1333-1343.
Probing the steric requirements of the γ-aminobutyric acid aminotransferase active site with fluorinated analogues of vigabatrin. Juncosa JI, Groves AP, Xia G, and Silverman RB. Bioorganic & Medicinal Chemistry. 2013 February 15;21(4):903-911.
View all publications by Richard B. Silverman in the National Library of Medicine (PubMed).