Insilico studies on anthrax lethal factor inhibitors: Pharmacophore modeling and virtual screening approaches towards designing of novel inhibitors for a killer

Roy, Jyoti; Kumar, Uday Chandra; Machiraju, Pavan Kumar; Muttineni, Ravi Kumar; Kumar, B.V.S. Suneel; Gundla, Rambabu; Dayam, Raveendra; Sarma, J. A. R. P.

doi:10.1016/j.jmgm.2010.07.002

Cited by 10 publications

(10 citation statements)

References 18 publications

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“…Accurate and validated pharmacophore hypotheses have proven useful for identifying new LF inhibitor scaffolds via database searching on the basis of ligand–receptor interactions observed for one or more series of active compounds (33, 36–38). 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.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

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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“…A model developed computationally by Roy et al used as a training set both reported hydroxamate analogs of L915 and a series of structurally unrelated furan derivatives reported by the Pellecchia group [53]. Their best model, which involved two hydrogen bond acceptors and two hydrophobic features, performed well in predicting the activity of a set of 98 reported inhibitors that were excluded from the training set ( R 2 = 0.77 for predicted activity vs. reported activity).…”

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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“…The resulting LF pharmacophore was used in a computational screen of a broad chemical library to identify chemically diverse leads that will be synthesized and evaluated [123]. Another study has analyzed pre-steady-state kinetics to investigate the binding of LF to substrates and hydroxymates [124].…”

Section: Current Research Directionsmentioning

confidence: 99%

New Developments in Vaccines, Inhibitors of Anthrax Toxins, and Antibiotic Therapeutics for Bacillus anthracis

Beierlein

Anderson²

2011

CMC

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Bacillus anthracis, the causative agent responsible for anthrax infections, poses a significant biodefense threat. There is a high mortality rate associated with untreated anthrax infections; specifically, inhalation anthrax is a particularly virulent form of infection with mortality rates close to 100%, even with aggressive treatment. Currently, a vaccine is not available to the general public and few antibiotics have been approved by the FDA for the treatment of inhalation anthrax. With the threat of natural or engineered bacterial resistance to antibiotics and the limited population for whom the current drugs are approved, there is a clear need for more effective treatments against this deadly infection. A comprehensive review of current research in drug discovery is presented in this article, including efforts to improve the purity and stability of vaccines, design inhibitors targeting the anthrax toxins, and identify inhibitors of novel enzyme targets. High resolution structural information for the anthrax toxins and several essential metabolic enzymes has played a significant role in aiding the structure-based design of potent and selective antibiotics.

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Insilico studies on anthrax lethal factor inhibitors: Pharmacophore modeling and virtual screening approaches towards designing of novel inhibitors for a killer

Cited by 10 publications

References 18 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

New Developments in Vaccines, Inhibitors of Anthrax Toxins, and Antibiotic Therapeutics for Bacillus anthracis

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