Substrate space analysis of the bacterial proton-coupled oligopeptide transporter YdgR by cheminformatics

Salvia Sajid, Marcus M.K. Nielsen, Ruqaiya Khalil, Paul R. Hansen, Henrik Franzyk, Mikkel Girke Jørgensen, Lars P. Christensen, Osman Mirza, Bala Krishna Prabhala*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


Proton-dependent oligopeptide transporters (POTs) are recognized for their substrate promiscuity due to their ability to transport a wide range of substrates. POTs are conserved in all forms of life ranging from bacteria to humans. A dipeptide-fluorophore conjugate, H-(β-Ala)-Lys(AMCA)-OH, is a well-known substrate of the transporter YdgR that is commonly used as a fluorescent reporter. In order to understand the substrate space of YdgR, we used this dipeptide as a bait reference, when screening an ensemble of compounds (previously tested in PEPT/PTR/NPF space) via a cheminformatic analysis based on the Tanimoto similarity index. Eight compounds (sinalbin, abscisic acid, carnosine, jasmonic acid, N-acetyl-aspartate, N-acetyl-lysine, aspartame, and N-acetyl-aspartylglutamate), covering a wide range on the Tanimoto scale, were tested for YdgR-mediated transport. Carnosine was the only compound observed to be a YdgR substrate based on cell-based transport assays and molecular docking. The other compounds tested were neither inhibitors nor substrates. Thus, we found that neither the Tanimoto similarity index nor ADME (absorption, distribution, metabolism, and excretion) properties appear useful for the identification of substrates (e.g., dipeptides) in YdgR-mediated drug transport.

Original languageEnglish
Article numberfnad052
JournalFEMS Microbiology Letters
Number of pages9
Publication statusPublished - 10. Jun 2023

Bibliographical note

Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS. All rights reserved.


  • POTs
  • Tanimoto similarity index
  • transport assays
  • YdgR


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