Identification of small-molecule inhibitors against SecA by structure-based virtual ligand screening

Evelien De Waelheyns, Kenneth Segers, Marios Frantzeskos Sardis, Jozef Anne, Gerry A. F. Nicolaes, Anastassios Economou*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


The rapid rise of antibiotic-resistant bacteria is one of the major concerns in modern medicine. Therefore, to treat bacterial infections, there is an urgent need for new antibacterials-preferably directed against alternative bacterial targets. One such potential target is the preprotein translocation motor SecA. SecA is a peripheral membrane ATPase and a key component of the Sec secretion pathway, the major route for bacterial protein export across or into the cytoplasmic membrane. As SecA is essential for bacterial viability, ubiquitous and highly conserved in bacteria, but not present in eukaryotic cells, it represents an attractive antibacterial target. Using an in silico approach, we have defined several potentially druggable and conserved pockets on the surface of SecA. We show that three of these potentially druggable sites are important for SecA function. A starting collection of similar to 500 000 commercially available small-molecules was virtually screened against a predicted druggable pocket in the preprotein-binding domain of Escherichia coli SecA using a multi-step virtual ligand screening protocol. The 1040 top-scoring molecules were tested in vitro for inhibition of the translocation ATPase activity of E. coli SecA. Five inhibitors of the translocation ATPase, and not of basal or membrane ATPase, were identified with IC50 values
Original languageEnglish
Pages (from-to)666-673
JournalJournal of Antibiotics
Issue number11
Publication statusPublished - Nov 2015


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