Research Article
Molecular Modelling Applied to the Computer-aided Design of Inhibitors of Mycobacterium Tuberculosis Aminoglycoside Acetyltransferase (Eis) to Combat Kanamycin Resistance
Bamba Ibrahim,
Kouadja Rika Justin,
Mousse Logbo Mathias,
Soro Issouf,
Niare Adama*,
Megnassan Eugene
Issue:
Volume 10, Issue 1, June 2026
Pages:
1-21
Received:
8 May 2026
Accepted:
19 May 2026
Published:
30 May 2026
DOI:
10.11648/j.ajcbe.20261001.11
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Abstract: Globally, tuberculosis continues to be a primary cause of death resulting from infectious diseases. The rise of resistant bacterial strains significantly undermines the effectiveness of current treatments. This study examines new sulfonamide derivatives (SULF) that target the Eis enzyme of Mycobacterium tuberculosis. This enzyme plays a direct role in kanamycin resistance. Three-dimensional models of the Eis-SULF complexes were generated from the reference crystal structure (PDB: 5IV0). These complexes were used to construct a test set of thirteen compounds with known experimental activities and an external validation set of four additional compounds. Active conformations were identified using energy-based QSAR modeling. The gas-phase model exhibits an R² coefficient of 0.96. Cross-validation of the gas-phase model yields an R²cv value of 0.95. The standard error of the gas-phase model is 0.28. The model in a solvated environment shows an R² value of 0.97. Cross-validation in a solvated environment yields an R²cv of 0.96. The standard error in a solvated environment is 0.24. A virtual library of sulfonamides was then constructed. The screening was based on Lipinski’s rules and the PH4 model. The PH4 model has an R² value of 0.91. The standard error of the PH4 model is 0.45. Sixty-five compounds show potential for oral bioavailability. The most promising complexes were studied using molecular dynamics. This analysis assesses the stability of ligands in the active site. The MM/GBSA approach was employed to calculate the binding free energies of the complexes. These calculations confirm a high affinity for the Eis enzyme. This integrated approach proposes promising new inhibitors against drug-resistant tuberculosis.
Abstract: Globally, tuberculosis continues to be a primary cause of death resulting from infectious diseases. The rise of resistant bacterial strains significantly undermines the effectiveness of current treatments. This study examines new sulfonamide derivatives (SULF) that target the Eis enzyme of Mycobacterium tuberculosis. This enzyme plays a direct role...
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