Development of a Comprehensive, Validated Pharmacophore Hypothesis for Anthrax Toxin Lethal Factor (LF) Inhibitors Using Genetic Algorithms, Pareto Scoring, and Structural Biology

Chiu, Ting Lan; Amin, Elizabeth A.

doi:10.1021/ci300121p

Cited by 11 publications

(12 citation statements)

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“…Several LF inhibitor pharmacophore hypotheses have been outlined in the literature (33, 36–38) ; however, these models were developed from relatively small training sets that occupy only one or two subsites of the LF active site and therefore do not necessarily represent the majority of key interactions that are essential for ligand binding. We recently reported (2) a new comprehensive pharmacophore map based on experimentally determined bound configurations for active compounds; this new hypothesis covers all three subsites (S1′, S1–S2, and S2′) of the LF active site and selectively identifies inhibitors with biological activity against LF in the nanomolar range. As reported by Chiu and Amin (2), for accurate and useful pharmacophore mapping based on active LF inhibitors, we recommend a genetic algorithm approach incorporating Pareto scoring, as implemented in the GALAHAD pharmacophore perception module (23) (see Note 1), together with ligand–receptor interaction analysis based on experimental structural biology (see Note 2).…”

Section: Methodsmentioning

confidence: 99%

“…We recently reported (2) a new comprehensive pharmacophore map based on experimentally determined bound configurations for active compounds; this new hypothesis covers all three subsites (S1′, S1–S2, and S2′) of the LF active site and selectively identifies inhibitors with biological activity against LF in the nanomolar range. As reported by Chiu and Amin (2), for accurate and useful pharmacophore mapping based on active LF inhibitors, we recommend a genetic algorithm approach incorporating Pareto scoring, as implemented in the GALAHAD pharmacophore perception module (23) (see Note 1), together with ligand–receptor interaction analysis based on experimental structural biology (see Note 2). …”

Section: Methodsmentioning

confidence: 99%

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Identification of Novel Anthrax Toxin Countermeasures Using In Silico Methods

Chiu

Maize

Amin

2013

Methods in Molecular Biology

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Anthrax is an acute infectious disease caused by the spore-forming, gram-positive, rod-shaped bacterium Bacillus anthracis. The anthrax toxin lethal factor (LF) is the primary anthrax toxin component responsible for cytotoxicity and host death and has been a heavily researched target for design of postexposure therapeutics in the event of a bioterror attack. Various computer-aided drug design methodologies have proven useful for pinpointing new antianthrax drug scaffolds, optimizing existing leads and probes, and elucidating key mechanisms of action. We present a selection of in silico virtual screening protocols incorporating docking and scoring, shape-based searching, and pharmacophore mapping techniques to identify and prioritize small molecules with potential biological activity against LF. We also recommend screening parameters that have been shown to increase the accuracy and reliability of these computational results.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Identification of Novel Anthrax Toxin Countermeasures Using In Silico Methods

Chiu

Maize

Amin

2013

Methods in Molecular Biology

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“…The Amin group also attempted to computationally define a universal LF active site inhibitor pharmacophore based on five reported inhibitors falling into three structural classes [54]. The resulting in silico screening model correctly identified 72% of the most potent experimentally identified LF inhibitors (IC 50 values in the nM range) and rejected all reported weakly active compounds (IC 50 values >100 µM).…”

Section: Identification Of Lf Inhibitors By Virtual Screeningmentioning

confidence: 99%

Inhibitors of the Metalloproteinase Anthrax Lethal Factor

Goldberg¹,

Turk

2016

CTMC

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Bacillus anthracis, a rod shaped, spore forming, gram positive bacteria, is the etiological agent of anthrax. B. anthracis virulence is partly attributable to two secreted bipartite protein toxins, which act inside host cells to disrupt signaling pathways important for host defense against infection. These toxins may also directly contribute to mortality in late stage infection. The zinc-dependent metalloproteinase anthrax lethal factor (LF) is a critical component of one of these protein toxins and a prime target for inhibitor development to produce anthrax therapeutics. Here, we describe recent efforts to identify specific and potent LF inhibitors. Derivatization of peptide substrate analogs bearing zinc-binding groups has produced potent and specific LF inhibitors, and X-ray crystallography of LF-inhibitor complexes has provided insight into features required for high affinity binding. Novel inhibitor scaffolds have been identified through several approaches, including fragment-based drug discovery, virtual screening, and high-throughput screening of diverse compound libraries. Lastly, efforts to discover LF inhibitors have led to the development of new screening strategies, such as the use of full-length proteins as substrates, that may prove useful for other proteases as well. Overall, these efforts have led to a collection of chemically and mechanistically diverse molecules capable of inhibiting LF activity in vitro and in cells, as well as in animal models of anthrax infection.

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“…A new pharmacophore map assembly designed to rapidly identify and prioritize promising LF inhibitor scaffolds from virtual compound libraries was reported (138). The authors utilized structural information from five available LF enzyme-inhibitor complexes deposited into the Protein Data Bank and considered all three key subsites of the LF catalytic binding region.…”

Section: Pa Lf and Ef As Antitoxin Design Targetsmentioning

confidence: 99%

Designing inhibitors of anthrax toxin

Nestorovich

Bezrukov

2014

Expert Opinion on Drug Discovery

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Introduction Present-day rational drug design approaches are based on exploiting unique features of the target biomolecules, small- or macromolecule drug candidates, and physical forces that govern their interactions. The 2013 Nobel Prize in chemistry awarded “for the development of multiscale models for complex chemical systems” once again demonstrated the importance of the tailored drug discovery that reduces the role of the trial and error approach to a minimum. The “rational drug design” term is rather comprehensive as it includes all contemporary methods of drug discovery where serendipity and screening are substituted by the information-guided search for new and existing compounds. Successful implementation of these innovative drug discovery approaches is inevitably preceded by learning the physics, chemistry, and physiology of functioning of biological structures under normal and pathological conditions. Areas covered This article provides an overview of the recent rational drug design approaches to discover inhibitors of anthrax toxin. Some of the examples include small-molecule and peptide-based post-exposure therapeutic agents as well as several polyvalent compounds. The review also directs the reader to the vast literature on the recognized advances and future possibilities in the field. Expert opinion Existing options to combat anthrax toxin lethality are limited. With the only anthrax toxin inhibiting therapy (PA-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, in our view, the situation is still insecure. The FDA’s animal rule for drug approval, which clears compounds without validated efficacy studies on humans, creates a high level of uncertainty, especially when a well-characterized animal model does not exist. Besides, unlike PA, which is known to be unstable, LF remains active in cells and in animal tissues for days. Therefore, the effectiveness of the post-exposure treatment of the individuals with anti-PA therapeutics can be time-dependent, requiring coordinated use of membrane permeable small-molecule inhibitors, which block the LF and EF enzymatic activity intracellularly. The desperate search for an ideal anthrax antitoxin allowed researchers to gain important knowledge of the basic principles of small-molecule interactions with their protein targets that could be easily transferred to other systems. At the same time, better identification and validation of anthrax toxin therapeutic targets at the molecular level, which include understanding of the physical forces underlying the target/drug interaction, as well as elucidation of the parameters determining the corresponding therapeutic windows, require further examination.

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Development of a Comprehensive, Validated Pharmacophore Hypothesis for Anthrax Toxin Lethal Factor (LF) Inhibitors Using Genetic Algorithms, Pareto Scoring, and Structural Biology

Cited by 11 publications

References 74 publications

Identification of Novel Anthrax Toxin Countermeasures Using In Silico Methods

Identification of Novel Anthrax Toxin Countermeasures Using In Silico Methods

Inhibitors of the Metalloproteinase Anthrax Lethal Factor

Designing inhibitors of anthrax toxin

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