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

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dc.contributor.authorBajaj, M.
dc.contributor.authorMamidyala, S.
dc.contributor.authorZuegg, J.
dc.contributor.authorBegg, S.
dc.contributor.authorWeen, M.
dc.contributor.authorLuo, Z.
dc.contributor.authorHuang, J.
dc.contributor.authorMcEwan, A.
dc.contributor.authorKobe, B.
dc.contributor.authorPaton, J.
dc.contributor.authorMcDevitt, C.
dc.contributor.authorCooper, M.
dc.date.issued2015
dc.description.abstractStreptococcus 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.
dc.description.statementofresponsibilityMegha Bajaj, Sreeman K. Mamidyala, Johannes Zuegg, Stephanie L. Begg, Miranda P. Ween, Zhenyao Luo, Johnny X. Huang, Alastair G. McEwan, Bostjan Kobe, James C. Paton, Christopher A. McDevitt, and Matthew A. Cooper
dc.identifier.citationACS Chemical Biology, 2015; 10(6):1511-1520
dc.identifier.doi10.1021/cb501032x
dc.identifier.issn1554-8929
dc.identifier.issn1554-8937
dc.identifier.orcidBegg, S. [0000-0002-7298-9335]
dc.identifier.orcidWeen, M. [0000-0002-0600-4585]
dc.identifier.orcidPaton, J. [0000-0001-9807-5278]
dc.identifier.orcidMcDevitt, C. [0000-0003-1596-4841]
dc.identifier.urihttp://hdl.handle.net/2440/100145
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.relation.granthttp://purl.org/au-research/grants/arc/DP120103957
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1022240
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/565526
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1071659
dc.rights© 2015 American Chemical Society
dc.source.urihttps://doi.org/10.1021/cb501032x
dc.subjectPsaA inhibitors
dc.titleDiscovery of novel pneumococcal surface antigen A (PsaA) inhibitors using a fragment-based drug design approach
dc.typeJournal article
pubs.publication-statusPublished

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