Ph.D., University of Groningen, Supervisor Prof. Ben L. Feringa (Nobel Laureate)
The students in the Arnold Group will learn different techniques of modern drug discovery. These include:
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.
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.
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.
The GABA(A) receptor is a pentameric membrane receptor that is expressed in neurons but also in many other cell types. The receptor respond to GABA with increased chloride influx causing hyperpolarization and therefore an increased cell membrane potential. This in turn regulates muscle function and immune response, two important hallmarks to combat asthma. Our group works together with the Cook Group who is responsible for the synthesis of new GABA(A) receptor ligands to overcome the pharmacological shortcomings of earlier ligands to develop a new systemic treatments for asthma. Important for our strategy is the inability of ligands to cross the blood-brain-barrier. Further pharmacological characterizations include pharmacokinetics and in vivo safety, selectivity towards the α4/5β3γ2 GABA(A) receptors, the ability to alleviate airway hyperresponsiveness and muscle constriction and reduce inflammation in the lung.
Mutchie T.R., Webb D.A., Di Milo E.S., Arnold L.A. "Strategies for the Design of Vitamin D Receptor Ligands". In: Badr M.Z. (eds) Nuclear Receptors. Springer, Cham. 2021, 199-217.
Olivia B. Yu, Daniel A. Webb, Elliot S. Di Milo, Tania R. Mutchie, Kelly A. Teske, Taosheng Chen, Wenwei Lin, Carole Peluso-Iltis, Natacha Rochel, Moritz Helmstädter, Daniel Merk and Leggy A. Arnold, “Biological Evaluation and Synthesis of Calcitroic Acid” Bioorganic Chemistry 2021, 116, 105310.
Nicolas M. Zahn, Brandon N. Mikulsky, M. S. Rashid Roni, Gene T. Yocum, Md Yeunus Mian, Daniel E. Knutson, James M. Cook, Charles W. Emala, Douglas C. Stafford, and Leggy A. Arnold “Nebulized MIDD0301 Reduces Airway Hyperresponsiveness in Moderate and Severe Murine Asthma Models” ACS Pharmacology & Translational Science 2020, 3(6), 1381-1390.
Guanguan Li, Amanda N. Nieman, Md Yeunus Mian, Nicolas M. Zahn, Brandon N. Mikulsky, Michael M. Poe, Kashi R. Methuku, Yongfeng Liu, James M. Cook, Douglas C. Stafford, and Leggy A. Arnold “A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor” Molecules 2020.
Daniel E. Knutson, M.S. Rashid Roni, Md Yeunus Mian, James M. Cook, Douglas C. Stafford, and Leggy A. Arnold “Improved scale-up synthesis and purification of clinical asthma candidate MIDD0301” Organic Process Research & Development 2020.
Amanda N. Nieman, Guanguan Li, Nicolas M. Zahn, Md Yeunus Mian, Brandon N. Mikulsky, Dylan A. Hoffman, Taylor M. Wilcox, Alexander S. Kehoe, Ian W. Luecke, Michael M. Poe, David Alvarez-Carbonell, James M. Cook, Douglas C. Stafford, Leggy A. Arnold "Targeting nitric oxide production in microglia with novel imidazodiazepines for non-sedative pain treatment" ACS Chemical Neuroscience 2020, 11(13), 2019-2013.
M.S. Rashid Roni, Guanguan Li, Brandon N. Mikulsky, Daniel E. Knutson, Md Yeunus Mian, Nicolas M. Zahn, James M. Cook, Douglas C. Stafford and Leggy A. Arnold "The effects of pH on the structure and bioavailability of imidazobenzo diazepine-3-carboxylate MIDD0301" Molecular Pharmaceutics 2020, 17(4), 1182-1192.
Olivia B. Yu, Tania R. Mutchie, Elliot S. Di Milo and Leggy A. Arnold, “Synthesis and biological evaluation of calcioic acid” Steroids 2020, 154, 108536.
Nicolas M. Zahn, Alec T. Huber, Brandon Nicholas Mikulsky, Mae Elizabeth Stepanski, Alexander Scott Kehoe, Guanguan Li, Melissa Schussman, M. S. Rashid Roni, Revathi Kodali, James M. Cook, Douglas C. Stafford, Douglas A. Steeber and Leggy A. Arnold "MIDD0301 ‒ A first-in-class anti-inflammatory asthma drug targets GABAA receptors without causing systemic immune suppression" Basic & Clinical Pharmacology & Toxicology 2019, 125, 75-84.
Tania R. Mutchie, Olivia B. Yu, Elliot S. Di Milo, and Leggy A. Arnold "Alternative binding sites at the vitamin D receptor and their ligands" Molecular and Cellular Endocrinology 2019, 485, 1-8.
Gloria S. Forkuo, Amanda N. Nieman, Revathi Kodali, Nicolas M. Zahn, Guanguan Li, M. S. Rashid Roni, Michael Rajesh Stephen, Ted W. Harris, Rajwana Jahan, Margaret L. Guthrie, Olivia B. Yu, Janet L. Fisher, Gene T. Yocum, Charles W. Emala, Douglas A. Steeber, Douglas C. Stafford, James M. Cook , and Leggy A. Arnold “A Novel Orally Available Asthma Drug Candidate That Reduces Smooth Muscle Constriction and Inflammation by Targeting GABA(A) Receptors in the Lung” Molecular Pharmaceutics 2018, 15, 1766-1777.
Kelly A. Teske, Jonathan W. Bogart and Leggy A. Arnold "Novel VDR antagonists based on the GW0742 scaffold" Bioorganic & Medicinal Chemistry Letters 2018, 28, 351-354.
Kelly A. Teske, Ganesha Rai, Premchendar Nandhikonda, Preetpal Sidhu, Belaynesh D. Feleke, Anton Simeonov, Adam Yasgar, Ajit Jadhav, David J. Maloney, and Leggy A. Arnold “A parallel chemistry approach to identify novel nuclear receptor ligands based on the GW0742 scaffold” ACS Combinatorial Chemistry 2017, 19, 646-656.
Gloria S. Forkuo, Amanda N. Nieman, Nina Y. Yuan, Revathi Kodali, Olivia B. Yu, Nicolas M. Zahn, Rajwana Jahan, Guanguan Li, Michael Rajesh Stephen, Margaret L. Guthrie, Michael M. Poe, Benjamin D. Hartzler, Ted W. Harris, Gene T. Yocum, Charles W. Emala, Douglas A. Steeber, Douglas C. Stafford, James M. Cook and Leggy A. Arnold “Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators” Molecular Pharmaceutics 2017. 14, 2088-2098.
Rajwana Jahan, Michael R Stephen, Gloria S Forkuo, Revathi Kodali, Margaret L Guthrie, Amanda N Nieman, Nina Y Yuan, Nicolas M Zahn, Michael M Poe, Guanguan Li, Olivia B Yu, Gene T Yocum, Charles W Emala, Douglas C Stafford, James M Cook, and Leggy A. Arnold "Optimization of Substituted Imidazobenzodiazepines as Novel Asthma Treatments" European Journal of Medicinal Chemistry 2017, 126, 550-560.
Olivia B. Yu, Leggy A. Arnold, “Calcitroic acid–a review” ACS Chemical Biology 2016, 11, 2665-2672.
Nina Y. Yuan, Michael M. Poe, Christopher Witzigmann, James M. Cook, Douglas Stafford, Leggy A. Arnold “Characterization of GABAA receptor ligands with automated patch-clamp using human neurons derived from pluripotent stem cells” Journal of Pharmacological and Toxicological Methods 2016, 82, 109-114.
Gloria S. Forkuo, Margaret L. Guthrie, Nina Y. Yuan, Amanda N. Nieman, Revathi Kodali, Rajwana Jahan, Michael R. Stephen, Gene T. Yocum, Marco Treven, Michael M. Poe, Guanguan Li, Olivia B.Yu, Benjamin D. Hartzler, Nicolas M. Zahn, Margot Ernst, Charles W. Emala, Douglas C. Stafford, James M. Cook, and Leggy A. Arnold “Development of GABA(A) Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma treatments” Molecular Pharmaceutics 2016, 13, 2026-2038.
Kelly A. Teske, Olivia Yu, and Leggy A. Arnold, “Inhibitors for the Vitamin D Receptor–Coregulator Interaction” Vitamin and Hormones 2016, 100, 45-82.
Kelly A.Teske, Jonathon W. Bogart, Luis M. Sanchez, Olivia B. Yu, Joshua V. Preston, James M. Cook, Nicholas R. Silvaggi, Daniel D. Bikle, and Leggy A. Arnold, “Synthesis and Evaluation of Vitamin D Receptor-Mediated Activities of Cholesterol and Vitamin D Metabolites" European Journal of Medicinal Chemistry 2016, 109, 238-246.