Toward the development of better therapeutic agents for Mycobacterium Tuberculosis: Computational design and evaluation of pyrazinone derivatives as inhibitors of enoyl acyl carrier protein reductase

The treatment of tuberculosis (TB) has become challenging, and efficient therapies need to be developed. Here, we apply in silico techniques to analyze the inhibitory role of pyrazinone derivatives toward enoyl-acyl carrier protein reductase (InhA) and compare our results with isoniazid, a well-known first-line TB drug. Docking suggests that despite binding within the same pocket, pyrazinone derivatives interact more strongly with InhA than isoniazid. Although C6 substitution does not significantly affect the ligand binding, N4-methoxybenzyl derivatives exhibit higher docking scores than their N4-ethyl counterparts. MD simulations suggest that the crucial interaction with Arg194 observed in the docked structures is mostly retained. In synchrony with MMGBSA binding energy calculations and QM calculations, analysis of the hydrogen bond occupancies and interaction energies reveal that pyrazinone derivatives with N4-methoxybenzyl substitution bind more strongly to InhA compared to N4-ethyl substituted derivatives. Our study thus identifies promising candidate compounds for potential inhibitory effects toward InhA.. KEYWORDS :Enoyl acyl carrier protein reductase, Molecular docking, Molecular dynamics simulations, Quantum mechanical calculations, Tuberculosis.