Cheminformatics-Driven Discovery of Selective, Nanomolar Inhibitors for Staphylococcal Pyruvate Kinase
Abstract
We have recently mapped the protein interaction network of methicillin-resistant Staphylococcus aureus (MRSA), which revealed its scale-free organization with characteristic presence of highly connected hub proteins that are critical for bacterial survival. Here we report the discovery of inhibitors that are highly potent against one such hub target, staphylococcal pyruvate kinase (PK). Importantly, the developed compounds demonstrate complete selectivity for the bacterial enzyme compared to all human orthologues. The lead 91nM inhibitor IS-130 has been identified through ligand-based cheminformatic exploration of a chemical space around micromolar hits initially generated by experimental screening. The following crystallographic study resulted in identification of a tetrameric MRSA PK structure where IS-130 is bound to the interface between the protein's subunits. This newly described binding pocket is not present in otherwise highly similar human orthologues and can be effectively utilized for selective inhibition of bacterial PK. The following synthetic modifications of IS-130, guided by structure-based molecular modeling, resulted in the development of MRSA PK inhibitors with much improved antimicrobial properties. Considering a notable lack of recent reports on novel antibacterial targets and cognate antibacterial compounds, this study provides a valuable perspective on the development of a new generation of antimicrobials. Equally noteworthy, the results of the current work highlight the importance of rigorous cheminformatics-based exploration of the results of high-throughput experiments.
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Numerous modulators have been developed to target PPIs, and many of them have successfully entered the clinic.
“To date, numerous modulators have been developed to target PPIs, and many of them have successfully entered the clinic.312–316”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [316]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- Axerio-Cilies, P., See, R. H., Zoraghi, R., Worral, L., Lian, T., Stoynov, N., Jiang, J., Kaur, S., Jackson, L., Gong, H., Swayze, R., Amandoron, E., Kumar, N. S., Moreau, A., Hsing, M., Strynadka, N. C., McMaster, W. R., Finlay, B. B., Foster, L. J., Young, R. N., Reiner, N. E., & Cherkasov, A.
- Affiliations
- University of British Columbia (CA)
- Simon Fraser University (CA)
- Vancouver Prostate Centre (CA)
- Corresponding author
- Reiner, Neil E.
- Cherkasov, Artem
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-11-21
- Volume
- 7
- Issue
- 2
- Pages
- 350-359
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W2073120190
- Cited by
- 31
- References
- 23
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 2 · 2017: 1 · 2015: 2 · 2014: 3 · 2013: 1 · 2012: 2
- FWCI
- 2.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Keywords
- methicillin-resistant Staphylococcus aureus, hub proteins, protein-protein interaction network, ligand-based virtual screening, cheminformatics, structure-based drug design, binding pocket, antimicrobial drug discovery
- MeSH terms
- Amino Acid Sequence, Anti-Bacterial Agents, Enzyme Inhibitors, Humans, Models, Molecular, Molecular Sequence Data, Pyruvate Kinase, Staphylococcal Infections, Sequence Alignment, Methicillin-Resistant Staphylococcus aureus, Drug Discovery, Protein Interaction Maps
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