TY - JOUR
T1 - A computational workflow to determine drug candidates alternative to aminoglycosides targeting the decoding center of E. coli ribosome
AU - Yuce, Merve
AU - Ates, Beril
AU - Yasar, Nesrin Isil
AU - Sungur, Fethiye Aylin
AU - Kurkcuoglu, Ozge
N1 - Publisher Copyright:
© 2024 Elsevier Inc.
PY - 2024/9
Y1 - 2024/9
N2 - 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.
AB - 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.
KW - 16S rRNA
KW - Antibiotic resistance
KW - Binding free energy
KW - Drug repurposing
KW - Molecular docking
KW - Molecular dynamics simulations
UR - http://www.scopus.com/inward/record.url?scp=85197535992&partnerID=8YFLogxK
U2 - 10.1016/j.jmgm.2024.108817
DO - 10.1016/j.jmgm.2024.108817
M3 - Article
C2 - 38976944
AN - SCOPUS:85197535992
SN - 1093-3263
VL - 131
JO - Journal of Molecular Graphics and Modelling
JF - Journal of Molecular Graphics and Modelling
M1 - 108817
ER -