Identification of potent phytochemical inhibitors against mobilized colistin resistance: Molecular docking, MD simulations, ADMET, and toxicity predictions

The rapid emergence of colistin resistance, primarily driven by the mobilized colistin resistance (MCR-1) gene, poses a significant threat to public health, undermining one of the last-resort antibiotics for multidrug-resistant infections. In this study, a comprehensive screening of 214 phytochemicals was conducted using molecular docking and molecular dynamics (MD) simulations to identify potent inhibitors of the MCR-1 receptor. Among the top-ranked compounds, ligand 1 (amentoflavone) and ligand 2 (hinokiflavone) exhibited the highest binding affinities, outperforming several known inhibitors, including epigallocatechin gallate and Sanguinarium. The docking analysis revealed strong hydrogen bonding and van der Waals interactions between ligand 1 and key active site residues such as SER-284, THR-283, and TYR-287, stabilizing the ligand in the MCR-1 binding pocket. In comparison, ligand 2 demonstrated fewer hydrogen bonds, resulting in slightly reduced binding stability. MD simulations confirmed the stability of both ligands, with ligand 1 maintaining a stable conformation throughout. ADMET analysis further supported the selection of ligand 1 (amentoflavone) and ligand 2 (hinokiflavone), highlighting their favourable pharmacokinetic profiles, including good absorption and high clearance rates. Toxicity predictions using Protox 3 revealed low overall toxicity (toxicity class 5) for amentoflavone (LD50: 3919 mg/kg) and hinokiflavone (LD50: 4000 mg/kg), with moderate risks of nephrotoxicity and respiratory toxicity, but low potential for carcinogenicity and mutagenicity. Despite these moderate toxicity flags, the strong binding affinity, structural stability, and drug-like properties of amentoflavone and hinokiflavone support their selection as lead scaffolds. This study underscores the potential of ligand 1 (amentoflavone) as a promising MCR-1 inhibitor and a natural starting point for further optimization in the development of anti-colistin resistance therapeutics.