Alexander Arnold (Leggy)

Photo of Alexander Arnold

Organic Chemistry
Assistant Professor
PhD, University of Groningen
(414) 229-2612
e-mail: arnold2@uwm.edu
Selected Publications

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.


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