Alexander A. Arnold

Alexander (Leggy) Arnold

Assistant Professor

Office: Chemistry 272C
Phone: 414-229-4411
e-mail: arnold2@uwm.edu

web: www.arnoldgroup.org

Degree(s):

Ph.D., University of Groningen

Research Description

Overview

Protein-protein interactions are essential for signal transduction in all living organisms. Many of these interactions have been revealed by means of biochemical assays but only a few interactions have been elucidated on a molecular level. The Arnold Group investigates small molecules with the ability to mimic the binding mode of short alpha-helical protein sequences. Examples are interactions between nuclear receptors (NRs) and transcriptional coregulators, which are essential for NR mediated gene regulation. The important role of nuclear receptors in human physiology is reflected by the fact that 20% of pharmaceutical prescriptions in the United States contain NR modulators. Due to the wide range of physiological processes regulated by NRs, small molecules targeting NRs often cause various side effects. Thus, there is still a great need for development of new approaches to regulating NR function.

Research

The vitamin D receptor (VDR) is one of 48 nuclear receptors identified in the human genome. Its structural organization consists of a ligand-independent transactivation domain (AF-1) at the amino terminus, a central DNA binding domain (DBD), and a ligand binding domain (LBD) including the allosteric ligand dependent activation function (AF-2). The binding of 1,25-Dihydroxyvitamin D3 to VDR activates specific gene regulation, which is governed by the recruitment of coregulators. The development of small molecules with the ability to inhibit the interaction between specific coregulators and VDR represents a new approach towards modulating NR signaling. The Arnold Group applies high-throughput screening, rational design, and virtual screening to discover VDR coregulator binding inhibitors (CBIs). Chemistry plays an essential role developing these molecules into biochemical probes allowing investigations of biological effects of specific VDR-coregulator inhibition in cells and organisms. Interestingly, these CBIs act complementary to the ligand based strategy to modulate VDR mediated signal transduction. The investigation of synergistic behavior between ligand and CBI might represent an important strategy to overcome hormone independent or hormone resistant NR signaling which represents a major problem for NR ligand based treatments such as cancer.

Education

The students in the Arnold Group will learn different techniques of modern drug discovery. These include:

  1. Assay development, high-throughput screening, data analysis, and data mining
  2. Hit compound validation using biochemical, biophysical and cell-based assays and determination of their mode of action
  3. Organic chemistry including the synthesis of bioactive scaffolds, hit compound structure-activity relationship studies (SAR), and parallel synthesis of small focused libraries in solution and on solid support
  4. Virtual screening, pharmacophore modeling and docking
  5. Pharmacological profiling of biomedical probes including ADME

The interdisciplinary research conducted in the Arnold Group combines the traditional fields of organic chemistry, biochemistry, analytical chemistry, and pharmacology to develop bioactive probes to investigate the underlying biomolecular pathways of human diseases.

Selected Publications

Premchendar Nandhikonda, Adam Yasgar, Athena M. Baranowski, Preetpal S. Sidhu, Megan M. McCallum, AlanJ. Pawlak, Kelly Teske, Belaynesh Feleke, Nina Y. Yuan, Chinedum Kevin, Daniel D. Bikle, Steven D. Ayers, Paul Webb, Ganesha Rai, Anton Simeonov, Ajit Jadhav, David Maloney, Leggy A. ArnoldPPARδ agonist GW0742 interacts weakly with multiple nuclear receptors including the vitamin D receptor” Biochemistry 2013, 52, 4193-4203.

Megan M. McCallum, Premchendar Nandhikonda, Jonathan J. Temmer, Charles Eyermann, Anton Simeonov, Ajit Jadhav, Adam Yasgar, David Maloney, Leggy A. Arnold ” High-Throughput Identification of Promiscuous Inhibitors from Screening Libraries with the Use of a Thiol-Containing Fluorescent Probe” J Biomol. Screen. 2013, 18(6), 705-713.  

Sourav Mukherjee , Alicia M. Hanson, William R. Shadrick, Jean Ndjomou, Noreena L. Sweeney, John J. Hernandez, Diana Bartczak, Kevin Li, Kevin J. Frankowski, Julie A. Heck, Leggy A. Arnold, Frank J. Schoenen, David N. Frick “Identification and analysis of hepatitis C virus NS3 helicase inhibitors using nucleic acid binding assays “ Nucleic Acids Res. 2012, 40(17), 8607-8621.

Premchendar Nandhikonda, Wen Z. Lynt, Megan M. McCallum, Tahniyath Ara, Athena M. Baranowski, Nina Y. Yuan, Dana Pearson, Daniel D. Bikle, R. Kiplin Guy, Leggy A. Arnold “Discovery of the First Irreversible Small Molecule Inhibitors of the Interaction between the Vitamin D Receptor and Coactivators” J Med Chem, 2012, 55(10), 4640-4651.

Richard G. Moore, Thilo S. Lange, Katina Robinson, Kyu K. Kim, Alper Uzun, Timothy C. Horan, Nada Kawar, Naohiro Yano, Sharon R. Chu, Quanfu Mao, Laurent Brard, Monique E. DePaepe, James F. Padbury, Leggy A. Arnold, Alexander Brodsky, Tun-Li Shen, Rakesh K. Singh “Efficacy of a Non-Hypercalcemic Vitamin-D2 Derived Anti-Cancer Agent (MT19c) and Inhibition of Fatty Acid Synthesis in an Ovarian Cancer Xenograft Model” PLOS one, 2012, 7(4), e34443.

Qin Chen, Peter D. Yim, Nina Yuan, Juliette Johnson, James M Cook, Steve Smith, Cristian Ionescu-Zanetti, Zhi-Jian Wang, Leggy A. Arnold, Charles W. Emala “Comparison of cell expression formats for the characterization the GABAA channels using a microfluidic patch clamp system” Assay Drug Dev. Technol. 2012, 10(4), 325-335.

Jennifer M. Atkinson, Anang A. Shelat, Angel Montero Carcaboso, Tanya A. Kranenburg, Leggy A. Arnold, Nidal Boulos, Karen Wright, Robert A. Johnson, Helen Poppleton, Kumarasamypet M. Mohankumar, Clementine Féau, Timothy Phoenix, Paul Gibson, Liqin Zhu, Yiai Tong, Chris Eden, David W. Ellison, Waldemar Priebe, Dimpy Koul, W. K. Alfred Yung, Amar Gajjar, Clinton F. Stewart, R. Kiplin Guy, Richard J. Gilbertson ”An Integrated In Vitro and In Vivo High-Throughput Screen Identifies Treatment Leads for Ependymoma” Cancer Cell, 2011, 20(3), 384-399.

Prabodh Sadana, Jong Yeon Hwang, Ramy R. Attia, Leggy A. Arnold, Geoffrey Neale, and R. Kiplin Guy “Similarities and Differences between Two Modes of Antagonism of the Thyroid Hormone Receptor” ACS Chemical Biology, 2011, 6(10), 1096-106.

Laurent Brard, Thilo S. Lange, Katina Robison, Kyu Kwang Kim, Tahniyath Ara, Megan Marie McCallum, Leggy A. Arnold, Richard G. Moore, Rakesh K. Singh “Evaluation of the first Ergocalciferol-derived, non hypercalcemic anti-cancer agent MT19c in ovarian cancer SKOV-3 cell lines” Gynecologic Oncology, 2011, 123(2), 370-8.

Jong Yeon Hwang, Wenwei Huang, Leggy A. Arnold, Ruili Huang, Michele Connelly, Jennifer Wichterman, Fangyi Zhu, Indre Augustinaite, Christopher P. Austin, James Inglese, Ronald L. Johnson, R. Kiplin Guy. “Methylsulfonylnitrobenzoates (MSNBs): A new class of irreversible inhibitors of the interaction of the thyroid hormone receptor and its obligate coactivators that functionally antagonizes thyroid hormone” J Biol Chem, 2011, 286(14), 11895-11908.

Ronald L. Johnson, Jong Yeon Hwang, Leggy A Arnold, Ruili Huang, Michele Connelly, Jennifer Wichterman, Fangyi Zhu, Indre Augustinaite, Christopher P. Austin, James Inglese, R. Kiplin Guy, Wenwei Huang. “A Quantitative High Throughput Screen Identifies Novel Inhibitors of the Interaction of Thyroid Receptor beta with a Peptide Ligand of Steroid Receptor Coactivator 2. J Biomol Screen, 2011, 16(6), 618-27.

Daniel D. Bikle, Arnaud Teichert, Leggy A. Arnold, Yoshikazu Uchida, Peter M. Elias, Yuko Oda. “Differential regulation of epidermal function by VDR coactivators” J Steroid Biochem Mol Biol. 2010, 121, 308-313.

Damon Reed, Ying Shen, Anang Shelat, Leggy A. Arnold, Antonio M. Ferreira, Fangyi Zhu, Nicolas Mills, David C. Smithson, Catherine A. Regni, Donald Bashford, Samatha A. Cicero, Brenda A. Schulman, Aart G. Jochemsen, R. Kiplin Guy. “Identification and characterization of the first small molecule inhibitor of MDMX” J. Biol. Chem. 2010, 285(14), 10786-96.

Books

Clémentine Féau, Leggy A. Arnold, Aaron Kosinski, and R. Kiplin Guy in Androgen Action, Chapter 4, “Ligand competition binding assay the androgen receptor” Methods in Molecular Biology 2011, 776, 59-68