Discovery of novel pneumococcal surface antigen A (PsaA) inhibitors using a fragment-based drug design approach

Bajaj, Megha, Mamidyala, Sreeman K., Zuegg, Johannes, Begg, Stephanie L., Ween, Miranda P., Luo, Zhenyao, Huang, Johnny Xiao, McEwan, Alastair G., Kobe, Bostjan, Paton, James C., McDevitt, Christopher A. and Cooper, Matthew A. (2015) Discovery of novel pneumococcal surface antigen A (PsaA) inhibitors using a fragment-based drug design approach. ACS Chemical Biology, 10 6: 1511-1520. doi:10.1021/cb501032x

Author Bajaj, Megha
Mamidyala, Sreeman K.
Zuegg, Johannes
Begg, Stephanie L.
Ween, Miranda P.
Luo, Zhenyao
Huang, Johnny Xiao
McEwan, Alastair G.
Kobe, Bostjan
Paton, James C.
McDevitt, Christopher A.
Cooper, Matthew A.
Title Discovery of novel pneumococcal surface antigen A (PsaA) inhibitors using a fragment-based drug design approach
Journal name ACS Chemical Biology   Check publisher's open access policy
ISSN 1554-8929
Publication date 2015-03
Sub-type Article (original research)
DOI 10.1021/cb501032x
Open Access Status
Volume 10
Issue 6
Start page 1511
End page 1520
Total pages 10
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2016
Language eng
Formatted abstract
Streptococcus pneumoniae is a leading cause of life-threatening bacterial infections, especially in young children in developing countries. Pneumococcal infections can be treated with β-lactam antibiotics, but rapid emergence of multidrug-resistant strains of S. pneumoniae over the past two decades has emphasized the need to identify novel drug targets. Pneumococcal surface antigen A (PsaA) is one such target, found on the cell surface of S. pneumoniae. It functions as a high-affinity substrate-binding protein, facilitating acquisition of Mn2+, which has an important role in protecting S. pneumoniae from reactive oxygen species and, hence, oxidative stress. Consequently, PsaA is essential for bacterial survival and an important virulence factor, which makes it a promising target for antibiotic drug development. To design novel PsaA inhibitors, we used a combination of de novo fragment-based drug discovery and in silico virtual screening methods. We profiled a collection of low molecular weight compounds that were selected based on their structural diversity and ability to bind to apo-PsaA in a virtual docking experiment. The screening resulted in two initial hits that were further optimized by structural variation to improve their potency while maintaining their ligand efficiency and favorable physicochemical properties. The optimized hits were validated using a cell-based assay and molecular dynamics simulations. We found that virtual screening substantially augmented fragment-based drug design approaches, leading to the identification of novel pneumococcal PsaA inhibitors.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
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Created: Fri, 10 Apr 2015, 09:24:08 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences