Discovery of potent triterpenoid and limonoid compounds targeting Mycobacterium tuberculosis enoyl acyl carrier protein reductase (InhA): An in silico investigation

Abstract

Drug resistance remains one of the primary concerns in treating tuberculosis (TB), making it imperative to find new and effective drug candidates for improved TB treatment. Enoyl acyl carrier protein reductase (InhA), an enzyme involved in mycolic acid biosynthesis, is crucial for anti-TB drug activity such as isoniazid (INH). Triterpenoids and limonoids are widespread in the plant kingdom and have gained much attention in their development as anti-TB agents. This study aims to examine the potential of triterpenoid and limonoid compounds as InhA inhibitors based on binding energy, interaction mode, and binding stability using docking and molecular dynamics (MD) investigation. Chisopatens A (−10.93 kcal/mol), 3-epi-cabraleahydroxy lactone (−9.85 kcal/mol), and 3-oxo-olean-11(12)en-28-oic acid (−9.73 kcal/mol), as well as 6α-(acetoxy)-14β,15β-epoxyazadirone (−9.77 kcal/mol), an azadirone-type limonoid derivative, have the best affinity for Leu63, Gly96, and Lys165 amino acid residues from InhA compared to native ligand (NAD) analyzed by docking studies. Chisopatens A, 3-epi-cabraleahydroxy lactone, and 3-oxo-olean-11(12)en-28-oic also had the best affinity for InhA based on MM-PBSA analysis, with values of −140.676 kJ/mol, −108.888 kJ/mol, and −162.605 kJ/mol, respectively. During dynamics studies, these compounds also showed good stability, protein compactness, and high-intensity interaction with InhA. These results strongly support future in-vitro studies to evaluate the efficacy of the hit compounds for treating INH-resistant MTB strains.