Inhibition enzymatique in silico des β- lactamases par Sedum sediforme

Abstract

Antibiotic resistance has now become a major public health challenge. Phytochemical compounds, particularly those derived from medicinal plants, influence the resistance mechanisms developed by bacteria. In this context, in silico approaches provide an effective alternative for predicting the affinity of natural compounds with β-lactamases. This study aims to identify bioactive molecules extracted from the plant Sedum sediforme using high-performance liquid chromatography (HPLC). This analysis revealed the presence of 17 phenolic compounds, with the most abundant being quercetin (36,52%) and gallic acid (24,11%). Other significant constituents included caffeic acid (6,65%), hesperetin (6,17%), syringic acid (5,47%), kaempferol (4,05%), and rutin (3,83%). The SDF structures of these molecules were downloaded from PubChem, optimized using Avogadro software, and then subjected to molecular docking targeting four representative β-lactamase proteins: TEM-1 (PDB: 1NYM), NDM-1 (PDB: 4EXS), AmpC (PDB: 1C3B), and OXA-48 (PDB: 7KHQ), using AMDock software. The results revealed notable binding affinities for certain ligand: quercetin with TEM-1: -8.9 kcal/mol, rutin with NDM-1: -6.79 kcal/mol, rutin with AmpC: -9.3 kcal/mol, gallic acid with OXA-48: -7.45 kcal/mol. Interaction analysis using BIOVIA Discovery Studio highlighted hydrogen bonds, hydrophobic interactions, and steric effects, stabilizing the protein-ligand complexes. A significant correlation was observed between ligand concentration and binding energy with TEM-1 (p = 0.023) and AmpC (p = 0.010). The ADME (Absorption, Distribution, Metabolism, Excretion) profiles of the top-performing ligands (those with the best docking scores) were generated using SwissADME. Gallic acid and quercetin comply with Lipinski’s rule of five, suggesting strong potential for oral administration. In contrast, rutin violates Lipinski’s rule. Applying the BOILED-Egg model, quercetin and gallic acid were located within the albumen zone, indicating their ability to cross the blood-brain barrier (BBB). Toxicological risk assessment using ProTox-3.0 revealed that quercetin, rutin, and gallic acid exhibit some organ-specific toxic effects. However, rutin displayed the highest LD₅₀ among the tested compounds, suggesting a lower toxic risk compared to the others.