Richard B. Silverman
Patrick G. Ryan/Aon 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.
Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease. Teixeira-Castro A, Jalles A, Esteves S, Kang S, da Silva Santos L, Silva-Fernandes A, Neto MF, Brielmann RM, Bessa C, Duarte-Silva S, Miranda A, Oliveira S, Neves-Carvalho A, Bessa J, Summavielle T, Silverman RB, Oliveira P, Morimoto RI, and Maciel P. Brain. 2015 November 1;138(11):3221-3237.
Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid. Lee H, Le HV, Wu R, Doud E, Sanishvili R, Kellie JF, Compton PD, Pachaiyappan B, Liu D, Kelleher NL, and Silverman RB. ACS Chemical Biology. 2015 September 1;10(9):2087-2098.
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.
2-Aminopyridines with a Truncated Side Chain to Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity. Kang S, Li H, Tang W, Martásek P, Roman LJ, Poulos TL, and Silverman RB. Journal of Medicinal Chemistry. 2015 July 23;58(14):5548-5560.
Inhibitor Bound Crystal Structures of Bacterial Nitric Oxide Synthase. Holden JK, Dejam D, Lewis MC, Huang H, Kang S, Jing Q, Xue F, Silverman RB, and Poulos TL. Biochemistry. 2015 July 7;54(26):4075-4082.
Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus. Holden JK, Kang S, Beasley FC, Cinelli MA, Li H, Roy SG, Dejam D, Edinger AL, Nizet V, Silverman RB, and Poulos TL. Chemistry & Biology. 2015 June 18;22(6):785-792.
Mechanism of Inactivation of Neuronal Nitric Oxide Synthase by (S)-2-Amino-5-(2-(methylthio)acetimidamido)pentanoic Acid. Tang W, Li H, Doud EH, Chen Y, Choing S, Plaza C, Kelleher NL, Poulos TL, and Silverman RB. Journal of the American Chemical Society. 2015 May 13;137(18):5980-5989.
Mechanistic Studies of Inactivation of Inducible Nitric Oxide Synthase by Amidines. Tang W, Li H, Poulos TL, and Silverman RB. Biochemistry. 2015 April 21;54(15):2530-2538.
Design and Mechanism of Tetrahydrothiophene-Based γ-Aminobutyric Acid Aminotransferase Inactivators. Le HV, Hawker DD, Wu R, Doud E, Widom J, Sanishvili R, Liu D, Kelleher NL, and Silverman RB. Journal of the American Chemical Society. 2015 April 8;137(13):4525-4533.
View all publications by Richard B. Silverman in the National Library of Medicine (PubMed).