A multi-stage computational pipeline and in vitro validation for the discovery of small-molecule translation inhibitors targeting the bacterial ribosome
Abstract
The global rise in antibiotic resistance necessitates new agents targeting essential bacterial processes like protein synthesis. Structure-based virtual screening enables the rapid identification of drug candidates from large chemical libraries, accelerating drug discovery. Here, we report an integrated computational and experimental pipeline to identify small-molecule translation inhibitors targeting the catalytic cavity of the E. coli ribosome. A consensus docking strategy using Glide and AutoDock Vina, combined with pharmacophore filtering and interaction analysis, was applied to FDA-approved, experimental, and investigational drug libraries to prioritize candidate compounds. The binding free energies of the compounds were estimated using restrained molecular dynamics (MD) simulations coupled with the MM-GBSA method, where the computational efficiency was improved by truncating the ribosome-ligand complexes. Guided by these results and our previous work on the E. coli 30S decoding center, 14 hit compounds were selected for the in vitro antibacterial and translation inhibition assays. Among these, Mitoxantrone (IC50 = 14.10 ± 0.38 µM) was identified as a translation inhibitor with a bacteriostatic effect comparable to the antibiotic Clindamycin. Whereas Plerixafor (IC50 = 62.30 ± 6.47 µM), Olcegepant (IC50 = 144.30 ± 16.41 µM), and Ziritaxestat (IC50 = 224.30 ± 25.02 µM) showed inhibitory effects at higher concentrations. Notably, Mitoxantrone has the potential to be an…
Read the paper
Related studies
- Meta-analysis of genome-wide association for migraine in six population-based European cohorts
- New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis
- microRNA profiling in atherosclerosis, diabetes, and migraine
- Genome‐Wide‐Associated Variants in Migraine Susceptibility: A Replication Study From North I ndia
- Pharmacoinformatics elucidation of potential drug targets against migraine to target ion channel protein KCNK18
- Upregulation of IL-1 Receptor Antagonist in a Mouse Model of Migraine
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.