A computational workflow to determine drug candidates alternative to aminoglycosides targeting the decoding center of E. coli ribosome.
J Mol Graph Model
; 131: 108817, 2024 Sep.
Article
in En
| MEDLINE
| ID: mdl-38976944
ABSTRACT
The global antibiotic resistance problem necessitates fast and effective approaches to finding novel inhibitors to treat bacterial infections. In this study, we propose a computational workflow to identify plausible high-affinity compounds from FDA-approved, investigational, and experimental libraries for the decoding center on the small subunit 30S of the E. coli ribosome. The workflow basically consists of two molecular docking calculations on the intact 30S, followed by molecular dynamics (MD) simulations coupled with MM-GBSA calculations on a truncated ribosome structure. The parameters used in the molecular docking suits, Glide and AutoDock Vina, as well as in the MD simulations with Desmond were carefully adjusted to obtain expected interactions for the ligand-rRNA complexes. A filtering procedure was followed, considering a fingerprint based on aminoglycoside's binding site on the 30S to obtain seven hit compounds either with different clinical usages or aminoglycoside derivatives under investigation, suggested for in vitro studies. The detailed workflow developed in this study promises an effective and fast approach for the estimation of binding free energies of large protein-RNA and ligand complexes.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ribosomes
/
Escherichia coli
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Molecular Dynamics Simulation
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Molecular Docking Simulation
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Aminoglycosides
Language:
En
Journal:
J Mol Graph Model
/
J. mol. graph. model
/
Journal of molecular graphics and modelling
Journal subject:
BIOLOGIA MOLECULAR
Year:
2024
Document type:
Article
Country of publication: