Inhibition of translation termination by small molecules targeting ribosomal release factors.

Ge X, Oliveira A, Hjort K, Bergfors T, Gutiérrez-de-Terán H, Andersson DI, Sanyal S, Åqvist J

Sci Rep 9 (1) 15424 [2019-10-28; online 2019-10-28]

The bacterial ribosome is an important drug target for antibiotics that can inhibit different stages of protein synthesis. Among the various classes of compounds that impair translation there are, however, no known small-molecule inhibitors that specifically target ribosomal release factors (RFs). The class I RFs are essential for correct termination of translation and they differ considerably between bacteria and eukaryotes, making them potential targets for inhibiting bacterial protein synthesis. We carried out virtual screening of a large compound library against 3D structures of free and ribosome-bound RFs in order to search for small molecules that could potentially inhibit termination by binding to the RFs. Here, we report identification of two such compounds which are found both to bind free RFs in solution and to inhibit peptide release on the ribosome, without affecting peptide bond formation.

Bioinformatics Compute and Storage [Service]

Drug Discovery and Development (DDD) [Service]

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PubMed 31659219

DOI 10.1038/s41598-019-51977-1

Crossref 10.1038/s41598-019-51977-1

pii: 10.1038/s41598-019-51977-1
pmc: PMC6817905