Multiscale in-silico profiling of phenoxy-acetamide: integrated ADME-Tox assessment, multi-target docking, molecular-dynamics validation, and Hirshfeld crystal analysis for antibacterial lead optimization.

Antimicrobial resistance is outpacing current therapies, motivating lean scaffolds for antibacterial discovery. We profiled phenoxy-acetamide M4 with an all-in-silico pipeline to connect electronic structure with binding and packing. Docking across five bacterial targets ranked the PBP3 pocket (PDB 7JWL) highest (-6.8 kcal mol-1), with other sites spanning -6.3 to -5.1 kcal mol-1. In 100-ns MD of the top complex, backbone mobility remained low, with ∼80 % of RMSF values in 0.05 0.20 nm, consistent with sustained engagement. DFT (HOMO/LUMO, ELF/LOL) supported dispersion-dominated recognition with selective, weak polar anchoring. Hirshfeld analysis quantified a compact, quasi-spherical surface (V = 411.5 Å3; A = 377.9 Å2; globularity = 0.708; asphericity = 0.110; V/A ≈ 1.09 Å) and a contact hierarchy dominated by H···H = 66.1 %, with C···H/H···C = 16.2 % and O···H/H···O = 15.4 %, indicating cohesion primarily from omnidirectional dispersion. Together, these multiscale read-outs assemble a consistent picture: M4 exhibits multitarget docking affinity and stable engagement driven by hydrophobic burial, while its solid-state surface metrics align with facile insertion into protein pockets prioritizing M4 for solubility-focused lead optimization and experimental validation.