- Poster presentation
- Open Access
Targeting protein-protein interactions using methods of cheminformatics
© Cherkasov; licensee BioMed Central Ltd. 2012
- Published: 1 May 2012
- Staphylococcus Aureus
- Pyruvate Kinase
- High Throughput Screening
- Protein Interaction Network
- Chemical Space
We have recently mapped the protein interaction networks of methicillin-resistant Staphylococcus aureus that revealed its scale-free organization with characteristic presence of highly-connected hub proteins that are critical for bacterial survival . Here we report the discovery of highly selective nanomolar inhibitors for one such hub target - staphylococcal pyruvate kinase. The lead compound has been identified through synergetic combination of methods of high-throughput screening and cheminformatics; its further synthetic modifications resulted in much improved antimicrobial properties. Further lead optimization yielded drug candidates with picomolar activity against methicillin-resistant Staphylococcus aureus.
Considering a notable lack of recent reports on novel antibacterial targets and cognate antibacterial compounds, this study provides a valuable perspective on the development of a new generation of antimicrobials. Equally noteworthy, the results of the current work highlight the importance of cheminformatics-driven exploration of chemical space around initial high throughput screening hits.
- Cherkasov A, Hsing M, Zoraghi R, Foster LJ, See RH, Stoynov N, Jiang J, Kaur S, Lian T, Jackson L, Gong H, Swayze R, Amandoron E, Hormozdiari F, Dao P, Sahinalp C, Santos-Filho O, Axerio-Cilies P, Byler K, McMaster WR, Brunham RC, Finlay BB, Reiner NE: . J Proteome Res. 2011, 10: 1139-1150. 10.1021/pr100918u.View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.