Rational design of indoleamine 2,3-dioxygenase inhibitors.

Indoleamine 2,3-dioxygenase (IDO) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. We have used the evolutionary docking algorithm EADock to design new inhibitors of this enzyme. First, we investigated the modes of binding of all known IDO inhibitors. On the basis of the observed docked conformations, we developed a pharmacophore model, which was then used to devise new compounds to be tested for IDO inhibition. We also used a fragment-based approach to design and to optimize small organic molecule inhibitors. Both approaches yielded several new low-molecular weight inhibitor scaffolds, the most active being of nanomolar potency in an enzymatic assay. Cellular assays confirmed the potential biological relevance of four different scaffolds.

Rational design of 4-aryl-1,2,3-triazoles for indoleamine 2,3-dioxygenase 1 inhibition.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. Starting from the scaffold of our previously discovered IDO1 inhibitor 4-phenyl-1,2,3-triazole, we used computational structure-based methods to design more potent ligands. This approach yielded highly efficient low molecular weight inhibitors, the most active being of nanomolar potency both in an enzymatic and in a cellular assay, while showing no cellular toxicity and a high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). A quantitative structure-activity relationship based on the electrostatic ligand-protein interactions in the docked binding modes and on the quantum chemically derived charges of the triazole ring demonstrated a good explanatory power for the observed activities.

Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator of immune responses and therefore an important therapeutic target for the treatment of diseases that involve pathological immune escape, such as cancer. Here, we describe a robust and sensitive high-throughput screen (HTS) for IDO1 inhibitors using the Prestwick Chemical Library of 1200 FDA-approved drugs and the Maybridge HitFinder Collection of 14,000 small molecules. Of the 60 hits selected for follow-up studies, 14 displayed IC50 values below 20 μM under the secondary assay conditions, and 4 showed an activity in cellular tests. In view of the high attrition rate we used both experimental and computational techniques to identify and to characterize compounds inhibiting IDO1 through unspecific inhibition mechanisms such as chemical reactivity, redox cycling, or aggregation. One specific IDO1 inhibitor scaffold, the imidazole antifungal agents, was chosen for rational structure-based lead optimization, which led to more soluble and smaller compounds with micromolar activity.

Eighty-Sixth General Assembly House Code of Ethics (House Resolution 5) Adopted 2-3-2015, February 3, 2015

Eighty-Sixth General Assembly House Code of Ethics (House Resolution 5) Adopted 2-3-2015. Every legislator and legislative employee has a duty to uphold the integrity and honor of the general assembly, to encourage respect for the law and for the general assembly, and to observe the house code of ethics. The members and employees of the house have a responsibility to conduct themselves so as to reflect credit on the general assembly, and to inspire the confidence, respect, and trust of the public. The following rules are adopted pursuant to chapter 68B of the Code, to assist the members and employees in the conduct of their activities.

Eighty-Sixth General Assembly House Rules (House Resolution 4-Adopted 2-3-2015), February 3, 2015

Eighty-Sixth General Assembly House Rules (House Resolution 4-Adopted 2-3-2015)

Eighty-Sixth General Assembly Joint Rules Governing Lobbyists (House Concurrent Resolution 7) House Adopted 2-3-2015, Senate Adopted 2-4-2015, February 5, 2015

Eighty-Sixth General Assembly Joint Rules Governing Lobbyists (House Concurrent Resolution 7) House Adopted 2-3-2015, Senate Adopted 2-4-2015

The Annals of Iowa, Spring/Summer 2006, Vol. 65, nos. 2-3

A quarterly journal of Iowa authors and their works produced by State Historical Society of Iowa. Special Commemorative Issue: Mormon Handcraft Trek

The Annals of Iowa, Spring/Summer 2008, Vol. 67, nos. 2&3

A quarterly journal of Iowa authors and their works produced by State Historical Society of Iowa.