Jana A. Lewis

The Design of Inhibitors for Medicinally Relevant Metalloproteins

A number of metalloproteins are important medicinal targets for conditions ranging from pathogenic infections to cancer. Many but not all of these metalloproteins contain a zinc(II) ion in the protein active site. Small‐molecule inhibitors of these metalloproteins are designed to bind directly to the active site metal ions. In this review several metalloproteins of interest are discussed, including matrix metalloproteinases (MMPs), histone deacetylases (HDACs), anthrax lethal factor (LF), and others. Different strategies that have been employed to design effective inhibitors against these proteins are described, with an effort to highlight the strengths and drawbacks of each approach. An emphasis is placed on examining the bioinorganic chemistry of these metal active sites and how a better understanding of the coordination chemistry in these systems may lead to improved inhibitors. It is hoped that this review will help inspire medicinal, biological, and inorganic chemists to tackle this important problem by considering all aspects of metalloprotein inhibitor design.

Evaluation and binding-mode prediction of thiopyrone-based inhibitors of anthrax lethal factor.

Anthrax lethal factor (LF) is one of three proteins involved in anthrax pathogenesis and lethality. Inactivation of the LF gene in B. anthracis leads to a decrease in virulence by 1000-fold or greater, which suggests that anthrax pathology is highly dependent on LF. Herein, we report an effective inhibitor of anthrax lethal factor based on a heterocyclic chelator scaffold. We also present computational predictions of the binding mode for this inhibitor and evidence that accurate prediction of binding modes requires use of a molecular surface-like boundary between solute and solvent. Anthrax LF is a zinc(II)-dependent, hydrolytic enzyme that cleaves the N terminus of the D domain of mitogen-activated protein kinase kinases (MAPKKs). This cleavage impairs essential signal transduction pathways and results in macrophage apoptosis along with other harmful consequences for the host. The potential for bioterrorism and inadequate treatments for anthrax, especially at late stages of infection, have amplified interest in finding effective anthrax lethal factor inhibitors (LFi). Several approaches have led to the identification of a variety of LFi, including library screening and optimization, fragment-based NMR screening (BI-11B3, Figure 1), mass-spectrometry-based screening, and re-examination of inhibitors of other metalloACHTUNGTRENNUNGproteinases and related hydroxamate-based compounds. An example of the latter class is the broad-spectrum matrix metalloproteinase inhibitor (MMPi) GM6001 (Figure 1), which was found to be an effective inhibitor of LF in vitro and in cell culture. Structural characterization of GM6001 in the LF active site shows that the hydroxamate group of the inhibitor

Synthesis, structure and spectroscopy of new thiopyrone and hydroxypyridinethione transition-metal complexes

The coordination chemistry of several O,S mixed donor ligands, namely thiopyrone and hydroxypyridinethione chelators, with a variety of middle and late first-row transition-metal ions is described. Complexes of 3-hydroxy-2-methyl-4-thiopyrone (thiomaltol) with cobalt(II), copper(II) and zinc(II); 3-hydroxy-1,2-dimethyl-4(1H)-pyridinethione (3,4-HOPTO) with iron(III), nickel(II), copper(II) and zinc(II); and 3-hydroxy-1-methyl-2(1H)-pyridinethione (3,2-HOPTO) with iron(III), nickel(II), copper(II) and zinc(II) have been synthesized and characterized. The structures, absorbance spectroscopy, cyclic voltammetry and superconducting quantum interferometer device (SQUID) measurements of selected metal complexes, as well as ligand protonation constants, are reported. Most of the metal complexes show coordination geometries indicative of a strong trans influence by the O,S chelators. The data presented herein provide the most detailed study of the transition-metal coordination chemistry of both thiopyrone and hydroxypyridinethione O,S donor ligands to date, and provide the basis for the investigation of these ligands in realm of biological inorganic chemistry.