Discovery of Acetylcholinesterase Peripheral Anionic Site Ligands through Computational Refinement of a Directed Library

Dickerson, Tobin J.; Beuscher, Albert E.; Rogers, Claude J.; Hixon, Mark S.; Yamamoto, Noboru; Xu, Yuanfu; Olson, and Arthur J.; Janda, Kim D.

doi:10.1021/bi051613x

Cited by 35 publications

(26 citation statements)

References 27 publications

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“…The study of small molecules that disrupt protein-protein interactions has evolved into a rich area, with molecules demonstrated to interrupt numerous systems of clinical significance (20)(21)(22)(23). It generally is accepted that the structural stability of protein-protein interactions derives from large, but relatively shallow, interfaces (24)(25)(26)(27) and that the difficulty in antagonizing interactions on such a large molecular scale has been linked to the size of the buried hydrophobic surfaces.…”

Section: Resultsmentioning

confidence: 99%

An in vitro and in vivo disconnect uncovered through high-throughput identification of botulinum neurotoxin A antagonists

Eubanks

Hixon

Jin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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117

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Among the agents classified as “Category A” by the U.S. Centers for Disease Control and Prevention, botulinum neurotoxin (BoNT) is the most toxic protein known, with microgram quantities of the protein causing severe morbidity and mortality by oral or i.v. routes. Given that this toxin easily could be used in a potential bioterrorist attack, countermeasures urgently are needed to counteract the pathophysiology of BoNT. At a molecular level, BoNT exerts its paralytic effects through intracellular cleavage of vesicle docking proteins and subsequent organism-wide autonomic dysfunction. In an effort to identify small molecules that would disrupt the interaction between the light-chain metalloprotease of BoNT serotype A and its cognate substrate, a multifaceted screening effort was undertaken. Through the combination of in vitro screening against an optimized variant of the light chain involving kinetic analysis, cellular protection assays, and in vivo mouse toxicity assays, molecules that prevent BoNT/A-induced intracellular substrate cleavage and extend the time to death of animals challenged with lethal toxin doses were identified. Significantly, the two most efficacious compounds in vivo showed less effective activity in cellular assays intended to mimic BoNT exposure; indeed, one of these compounds was cytotoxic at concentrations three orders of magnitude below its effective dose in animals. These two lead compounds have surprisingly simple molecular structures and are readily amenable to optimization efforts for improvements in their biological activity. The findings validate the use of high-throughput screening protocols to define previously unrecognized chemical scaffolds for the development of therapeutic agents to treat BoNT exposure.

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Section: Resultsmentioning

confidence: 99%

An in vitro and in vivo disconnect uncovered through high-throughput identification of botulinum neurotoxin A antagonists

Eubanks

Hixon

Jin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

117

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“…The AutoDock Software suite has been used successfully to find inhibitors from chemical databases (Li et al, 2004;Dickerson et al, 2005;Rogers et al, 2006). The accuracy of VLS is limited by the structural information for the protein target.…”

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confidence: 99%

Stabilizers of the Max Homodimer Identified in Virtual Ligand Screening Inhibit Myc Function

et al. 2009

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Many human cancers show constitutive or amplified expression of the transcriptional regulator and oncoprotein Myc, making Myc a potential target for therapeutic intervention. Here we report the down-regulation of Myc activity by reducing the availability of Max, the essential dimerization partner of Myc. Max is expressed constitutively and can form unstable homodimers. We have isolated stabilizers of the Max homodimer by applying virtual ligand screening (VLS) to identify specific binding pockets for small molecule interactors. Candidate compounds found by VLS were screened by fluorescence resonance energy transfer, and from these screens emerged a potent, specific stabilizer of the Max homodimer. In vitro binding assays demonstrated that the stabilizer enhances the formation of the Max-Max homodimer and interferes with the heterodimerization of Myc and Max in a dose-dependent manner. Furthermore, this compound interferes with Myc-induced oncogenic transformation, Myc-dependent cell growth, and Myc-mediated transcriptional activation. The Max-Max stabilizer can be considered a lead compound for the development of inhibitors of the Myc network.

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“…They have no structural similarity to ACh, the substrate for the enzyme. The size of the AChE catalytic pocket is 1.8 nm, 46 but the diameter of a dendrimer molecule ranges from 4.2 nm to 5 nm for generations 3 and 4, respectively. 66 Therefore, it seems likely that cationic phosphorus dendrimers do not interact directly with the catalytic pocket of the enzyme but change the conformation of the protein, modify the parameters of the plasma membrane or interact with other protein components of the membrane.…”

Section: Resultsmentioning

confidence: 99%

Cationic phosphorus dendrimers and therapy for Alzheimer's disease

et al. 2015

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Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the aggregation of extracellular b-amyloid and the intracellular microtubule-associated protein Tau. Neurodegeneration is associated inter alia with the activation of microglial cells, neuroinflammation, oxidative stress, and diminished transduction of impulses in cholinergic neurons. Current pharmacotherapy for AD is based mainly on modulation of acetylcholine hydrolysis, administration of non-steroidal anti-inflammatory drugs and antioxidants. Novel drugs with antiamyloidic properties are currently being sought. Cationic phosphorus dendrimers have been proven to modulate amyloidogenesis and stop the aggregation of Tau protein. An ideal drug for AD should demonstrate anti-inflammatory properties, inhibit acetylcholine hydrolysis, and have antioxidant capacity. Cationic phosphorus dendrimers (generation 3 and generation 4) show the foregoing properties. They inhibit acetylcholinesterase activity, can decrease the secretion of TNF-a, and have weak antioxidant effects. The results presented suggest that phosphorus dendrimers may be considered in the future as agents in AD therapy.

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Discovery of Acetylcholinesterase Peripheral Anionic Site Ligands through Computational Refinement of a Directed Library

Cited by 35 publications

References 27 publications

An in vitro and in vivo disconnect uncovered through high-throughput identification of botulinum neurotoxin A antagonists

An in vitro and in vivo disconnect uncovered through high-throughput identification of botulinum neurotoxin A antagonists

Stabilizers of the Max Homodimer Identified in Virtual Ligand Screening Inhibit Myc Function

Cationic phosphorus dendrimers and therapy for Alzheimer's disease

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