Research Article

Muhammad Osama Sajjad

Published on : December 2025 | Volume : 2 Issue : 2

Abstract :

Antimicrobial resistance driven by β-lactamase enzymes is a growing threat to global health. Among these enzymes, AmpC β-lactamase plays a major role in resistance to broad-spectrum β-lactam antibiotics in Gram-negative pathogens. Morganella morganii is an emerging opportunistic pathogen associated with urinary tract, wound, and nosocomial infections. However, structural and dynamic insights into its AmpC enzyme remain limited, restricting rational inhibitor design. This study aimed to resolve the structural architecture of M. morganii AmpC and identify potential inhibitory compounds using an integrated computational workflow. The AmpC sequence (UniProt ID: P94958) was analyzed for physicochemical and immunological properties. The protein contains 379 amino acids with an estimated molecular weight of ~41.27 kDa and theoretical pI of 8.69. Antigenicity prediction indicated a probable antigenic profile (score: 0.4498), while allergenicity analysis classified the protein as non-allergenic. Comparative homology modeling using multiple platforms generated a highquality three-dimensional structure, with ~90% residues located in favored Ramachandran regions, confirming structural reliability. The Phyre2-derived model showed optimal query coverage and structural integrity. Virtual screening of 21 compounds identified Oncoglabrinol C as the strongest binder, with binding energy of -11.44 kcal/mol and inhibition constant of 4.09 nM. The ligand formed stable hydrogen bonds with catalytic residues including Glu80, Arg147, Arg229, Val230, and Gln234, along with π–π interactions involving Tyr189 and Tyr240. Molecular dynamics simulations of the AmpC–Oncoglabrinol C complex over 100ns demonstrated structural stability. RMSD stabilized near 6 Å after 80 ns, while radius of gyration decreased from ~22.6 Å to ~20.6 Å, indicating increased protein compactness. Hydrogen bonding remained stable throughout the simulation. MM/PBSA and MM/GBSA energy analyses confirmed sustained ligand binding and favorable interaction energetics. Collectively, these results provide detailed structural and mechanistic insights into AmpC β-lactamase from M. morganii and identify Oncoglabrinol C as a promising lead compound for inhibitor development. This work supports structure-guided drug discovery targeting AmpC-mediated β-lactam resistance.