Targeting plague virulence factors: a combined machine learning method and multiple conformational virtual screening for the discovery of Yersinia protein kinase A inhibitors.

@article{Hu2007TargetingPV,
  title={Targeting plague virulence factors: a combined machine learning method and multiple conformational virtual screening for the discovery of Yersinia protein kinase A inhibitors.},
  author={Xin Hu and Gerd Prehna and C. Erec Stebbins},
  journal={Journal of medicinal chemistry},
  year={2007},
  volume={50 17},
  pages={
          3980-3
        }
}
Yersinia spp. is currently an antibiotic resistance concern and a re-emerging disease. The essential virulence factor Yersinia protein kinase A (YpkA) contains a Ser/Thr kinase domain whose activity modulates pathogenicity. Here, we present an approach integrating a machine learning method, homology modeling, and multiple conformational high-throughput docking for the discovery of YpkA inhibitors. These first reported inhibitors of YpkA may facilitate studies of the pathogenic mechanism of YpkA… 

Figures from this paper

Enzyme Activity Assays for Protein Kinases: Strategies to Identify Active Substrates.
TLDR
Strategies and successes in the identification of alternative substrates for kinases from organisms responsible for many of the neglected tropical diseases (NTDs) are reviewed towards the goal of informing strategies to identify substrate for new kinases.
Biased retrieval of chemical series in receptor-based virtual screening
TLDR
It is highlighted that much of the early enrichment in the DUD dataset is the result of retrieval of a single cluster of active compounds, not necessarily due to early enrichment of the cluster containing the co-crystallized ligand.
Artificial Intelligence and Antibiotic Discovery
TLDR
Cheaper and faster research can be achieved through algorithms that identify hit compounds, thereby further accelerating the development of new antibiotics, which represents a vital step in solving the current antibiotic crisis.
Lead Discovery Using Virtual Screening
TLDR
It is argued that the capability of VS methods has grown to a point where fuller integration with experimental methods, including HTS, could increase the effectiveness of both.
Combined Virtual Screening Strategies
TLDR
This review discusses recent 2D/3D QSAR and ligand-based/target-based “synergistic” combinations that allow speeding-up the VS process, permitting accurate and efficient studies on large databases.
Chemical space sampling by different scoring functions and crystal structures
TLDR
Different crystal structures and different scoring functions are complementary to each other and allow for a wider variety of chemotypes to be considered for experimental follow-up.
New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays.
TLDR
A number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens are described.
Receptor Flexibility in Ligand Docking and Virtual Screening
TLDR
An overview of existing approaches to treating receptor flexibility in protein-ligand docking and virtual screening that range from approximate to more accurate methods, including the use of normal modes in accounting for global conformational changes of the receptor or the useof more precise force fields are given.
Optimization of molecular docking scores with support vector rank regression
TLDR
The results suggested that, with additional features to indicate the comparative fitness between computed binding conformations, the SVRR algorithm holds the potential to create a new category of more accurate integrative docking scores.
...
...

References

SHOWING 1-10 OF 24 REFERENCES
Targeting virulence for antibacterial chemotherapy: identifying and characterising virulence factors for lead discovery.
TLDR
It might be the case that virulence target-based therapies would not be powerful enough to clear an existing infection alone, but if they are instead considered as adjunct therapy to existing antibiotics, or potentiators of the host immune response, they may show efficacy in a non-traditional way.
Targeting Virulence for Antibacterial Chemotherapy
TLDR
It might be the case that virulence target-based therapies would not be powerful enough to clear an existing infection alone, but if they are instead considered as adjunct therapy to existing antibiotics, or potentiators of the host immune response, they may show efficacy in a non-traditional way.
Protein kinase inhibition: different approaches to selective inhibitor design.
TLDR
The purpose of this review is to offer the reader an idea of the evolution of the methodologies utilized in the quest for selective kinase inhibitors, from the more traditional, screening-based methods to the newer technology of chemogenomics, proteomics and chemical genetics.
Inhibition of Protein Kinase CK2 by Anthraquinone-related Compounds
TLDR
Three new crystal structures of ATP site-directed inhibitors in complex with “casein kinase-2” (CK2), a constitutively active protein kinase implicated in a variety of cellular functions and misfunctions are presented and discussed.
A distinctive role for the Yersinia protein kinase: actin binding, kinase activation, and cytoskeleton disruption.
TLDR
It is demonstrated that Yersinia protein kinase A (YpkA), an essential bacterial virulence factor, is produced as an inactive serine/threonine kinase that functions within cultured epithelial cells to disrupt the actin cytoskeleton.
Virtual screening for kinase targets.
TLDR
To illustrate the challenges and pitfalls of virtual screening for kinase targets, a case study of finding irreversible inhibitors of ErbB2 through in silico screening is presented and the question of how ranking is influenced by the database screened is focused on.
Protein Kinase Inhibitors: Insights into Drug Design from Structure
TLDR
This review focuses on kinase inhibitors that are in the clinic or in clinical trials and for which structural information is available and which have provided insights into targeting the inactive or active form of the kinase, for targeting the global constellation of residues at the ATP site, and into targeting noncatalytic domains.
...
...