Structure-Based Discovery Of Marine Natural Inhibitors Against AMPC Β-Lactamase Of Burkholderia Multivorans: An In Silico Pharmacological And Dynamic Simulation Study

Abstract

The alarming rise of antibiotic resistance in Burkholderia multivorans has been closely linked to the expression of AmpCβ-lactamase. This study aimed to identify potential marine-derived inhibitors targeting this enzyme through a comprehensive in silico approach. The functional role of AmpC was explored via KEGG and STRING databases, revealing its involvement in β-lactam resistance pathways and key protein–protein interactions. The crystal structure of AmpC (PDB ID: 3W4Q) was refined and validated before being subjected to site-directed virtual screening. A library of 60 filtered marine natural compounds from the CMNPD database was screened using AutoDock Vina, guided by CASTp-predicted active sites. Top hits were evaluated for binding affinity, drug-likeness, ADMET properties, and cardiotoxic risk using SwissADME and PRED-hERG tools. Among the shortlisted compounds, oplopanone and ellagic acid showed strong binding affinities, with oplopanone displaying the most stable interaction (−8.13 kcal/mol). Molecular dynamics simulations of the AmpC-oplopanone complex over 50 ns confirmed its dynamic stability and favorable interaction profile under physiological conditions. These results highlight oplopanone and ellagic acid as promising lead compounds for further in vitro and in vivo validation in the development of novel β-lactamase inhibitors.