Structure-based virtual screening and MD refinement reveal novel inhibitors of Escherichia coli arginyl-tRNA synthetase

Abstract

Interfering with the catalytic cycle or targeting the catalytic center of key enzymes has been an important strategy in medicinal research. Rapidly increasing drug resistance in Escherichia coli poses a significant threat to the healthcare system globally. This study utilized a multi-tier in silico pipeline to explore and optimize anthraquinone-based inhibitors of E. coli arginyl-tRNA synthetase (eArgRS). High-throughput virtual screening, docking and SIFt interaction profiling highlighted our top-scoring hits, CID100282 and CID135468, which share an anthraquinone core. Detailed molecular dynamics simulations showed that these two leading compounds bind stably inside eArgRS catalytic pocket and identified Asp118 as the principal energetic hotspot. MM/GBSA calculations on the equilibrated trajectories yielded favorable ΔG_bind values (−14.7 and −25 kcal mol⁻¹, respectively) driven by electrostatics and compensated polar solvation. Per-residue energy decomposition pinpointed Asp118, Asp317/Glu258, Tyr313/Tyr335, and Ile337 as dominant contributors, validating an electrostatic-hydrophobic clamp mechanism. Structure–activity exploration of the variable R₁–R₅ fragments around the rigid anthraquinone scaffold suggested polar donors at R₁/R₂, and aromatic acceptors at R₃ maximized triad engagement while minimizing desolvation. These insights lay the foundation for the development of potent and optimized eArgRS inhibitors having terminal basic motifs interacting with acidic residues within the active site.