Exploring species-specific inhibitors with multiple target sites on S. aureus pyruvate kinase using a computational workflow

Merve Yuce, Zehra Sarica, Beril Ates, Ozge Kurkcuoglu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Experimental evidence indicated that bacterial pyruvate kinase of glycolysis can be evaluated as an alternative target to eliminate infections, while antibiotic resistance poses a global threat. Here, we use a computational workflow to reveal and investigate the potential allosteric sites of methicillin-resistant S. aureus PK, which can help in designing species-specific drugs to inhibit activity of this organism. Residue interaction networks point to a known allosteric site at the small C-C interface, a potential allosteric site near the small interface (site #1), and a second potential allosteric site at the large interface (site #2). 2 µs-long molecular dynamics (MD) simulations with AMBER16 generate different conformations of one narrow target site. Known and potential allosteric sites on the selected conformers are investigated using ensemble docking with AutoDock Vina and a library of 2447 FDA-approved drugs. We determine 18 hits, comprising ergot-alkaloids, anti-cancer-agents, antivirals, analgesics, cardiac glycosides, all with a high docking z-score for three sites. 5 selected compounds with high, average and low z-scores are subjected to 50 ns-long MD simulations for MM-GBSA calculations. ΔGbind values up to −49.3 kcal/mol at the C-C interface, up to −32.7 kcal/mol at site #1, and up to −53.3 kcal/mol at site #2 support the docking calculations. We investigate mitapivat and TT-232 as reference compounds under clinical trial, targeting human PK isomers. We suggest 18 FDA-approved hits from the docking calculations and TT-232 as potential inhibitors with multiple target sites on S. aureus PK. This study also proposes pharmacophores models for de novo drug design. Communicated by Ramaswamy H. Sarma.

Original languageEnglish
Pages (from-to)3496-3510
Number of pages15
JournalJournal of Biomolecular Structure and Dynamics
Volume41
Issue number8
DOIs
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© 2022 Informa UK Limited, trading as Taylor & Francis Group.

Funding

The authors thank Erdem Cicek for his support for the MD simulations. Computing resources used in this work were provided by the National Center for High Performance Computing of Turkey (UHeM) under grant number 1009292021. This work is supported by the Scientific and Technological Research Council of Turkey (TÜBİTAK) Project No. 218M320. BA thanks to the 2020-TÜBİTAK STAR Scholarship. The authors thank Erdem Cicek for his support for the MD simulations. Computing resources used in this work were provided by the National Center for High Performance Computing of Turkey (UHeM) under grant number 1009292021.

FundersFunder number
National Center for High Performance Computing of Turkey
Ulusal Yüksek Başarımlı Hesaplama Merkezi, Istanbul Teknik Üniversitesi1009292021
Türkiye Bilimsel ve Teknolojik Araştırma Kurumu218M320

    Keywords

    • allostery
    • drug repurposing
    • glycolytic pathway
    • molecular dynamics simulations
    • Residue interaction networks

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