Identification of potent phytochemical inhibitors against mobilized colistin resistance: Molecular docking, MD simulations, ADMET, and toxicity predictions
Himanshu Jangid, Nusrat Hamid Shah, Mudasir A. Dar, Atif Khurshid Wani
Abstract
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.