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dc.contributor.authorBajaj, M.en
dc.contributor.authorMamidyala, S.en
dc.contributor.authorZuegg, J.en
dc.contributor.authorBegg, S.en
dc.contributor.authorWeen, M.en
dc.contributor.authorLuo, Z.en
dc.contributor.authorHuang, J.en
dc.contributor.authorMcEwan, A.en
dc.contributor.authorKobe, B.en
dc.contributor.authorPaton, J.en
dc.contributor.authorMcDevitt, C.en
dc.contributor.authorCooper, M.en
dc.identifier.citationACS Chemical Biology, 2015; 10(6):1511-1520en
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.en
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. Cooperen
dc.publisherAmerican Chemical Societyen
dc.rights© 2015 American Chemical Societyen
dc.subjectPsaA inhibitorsen
dc.titleDiscovery of novel pneumococcal surface antigen A (PsaA) inhibitors using a fragment-based drug design approachen
dc.typeJournal articleen
pubs.library.collectionMolecular and Biomedical Science publicationsen
dc.identifier.orcidBegg, S. [0000-0002-7298-9335]en
dc.identifier.orcidWeen, M. [0000-0002-0600-4585]en
dc.identifier.orcidPaton, J. [0000-0001-9807-5278]en
dc.identifier.orcidMcDevitt, C. [0000-0003-1596-4841]en
Appears in Collections:Molecular and Biomedical Science publications

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