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
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.