Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A.

Botulinum neurotoxins have remarkable persistence (∼weeks to months in cells), outlasting the small-molecule inhibitors designed to target them. To address this disconnect, inhibitors bearing two pharmacophores-a zinc binding group and a Cys-reactive warhead-were designed to leverage both affinity and reactivity. A series of first-generation bifunctional inhibitors was achieved through structure-based inhibitor design.

Ligand-induced expansion of the S1' site in the anthrax toxin lethal factor.

The Bacillus anthracis lethal factor (LF) is one component of a tripartite exotoxin partly responsible for persistent anthrax cytotoxicity after initial bacterial infection. Inhibitors of the zinc metalloproteinase have been investigated as potential therapeutic agents, but LF is a challenging target because inhibitors lack sufficient selectivity or possess poor pharmaceutical properties. These structural studies reveal an alternate conformation of the enzyme, induced upon binding of specific inhibitors, that opens a previously unobserved deep pocket termed S1'(∗) which might afford new opportunities to design selective inhibitors that target this subsite.

Probing the S2' Subsite of the Anthrax Toxin Lethal Factor Using Novel N-Alkylated Hydroxamates.

The lethal factor (LF) enzyme secreted by Bacillus anthracis is a zinc hydrolase that is chiefly responsible for anthrax-related cell death. Although many studies of the design of small molecule LF inhibitors have been conducted, no LF inhibitor is yet available as a therapeutic agent. Inhibitors with considerable chemical diversity have been developed and investigated; however, the LF S2' subsite has not yet been systematically explored as a potential target for lead optimization.

Anthrax toxin lethal factor domain 3 is highly mobile and responsive to ligand binding.

The secreted anthrax toxin consists of three components: the protective antigen (PA), edema factor (EF) and lethal factor (LF). LF, a zinc metalloproteinase, compromises the host immune system primarily by targeting mitogen-activated protein kinase kinases in macrophages. Peptide substrates and small-molecule inhibitors bind LF in the space between domains 3 and 4 of the hydrolase.

Analysis of the Errors in the Electrostatically Embedded Many-Body Expansion of the Energy and the Correlation Energy for Zn and Cd Coordination Complexes with Five and Six Ligands and Use of the Analysis to Develop a Generally Successful Fragmentation Strategy.

In the present paper, we apply the electrostatically embedded many-body expansion of the correlation energy (EE-MB-CE) to the calculation of zinc-ligand and cadmium-ligand bond dissociation energies, and we analyze the errors due to various fragmentation schemes in a variety of neutral, positively charged, and negatively charged Zn and Cd coordination complexes. As a result of the analysis, we are able to present a new, simple, and unambiguous fragmentation strategy. Following this strategy, we show that both methods perform well for zinc-ligand and cadmium-ligand bond dissociation energies for all systems studied in the paper, including a model of the catalytic site of the zinc-bearing anthrax toxin lethal factor (LF), which has garnered substantial attention as a target for drug development.

Electrostatically Embedded Many-Body Expansion for Neutral and Charged Metalloenzyme Model Systems.

The electrostatically embedded many-body (EE-MB) method has proven accurate for calculating cohesive and conformational energies in clusters, and it has recently been extended to obtain bond dissociation energies for metal-ligand bonds in positively charged inorganic coordination complexes. In the present paper, we present four key guidelines that maximize the accuracy and efficiency of EE-MB calculations for metal centers. Then, following these guidelines, we show that the EE-MB method can also perform well for bond dissociation energies in a variety of neutral and negatively charged inorganic coordination systems representing metalloenzyme active sites, including a model of the catalytic site of the zinc-bearing anthrax toxin lethal factor, a popular target for drug development.