Imidazooxazine moiety as polyketide synthase 13 inhibitors targeting tuberculosis

Abstract

Recently, imidazooxazines have attracted more attention due to their therapeutic potential against tuberculosis (TB). The present study aimed to identify and develop potential inhibitors against Pks13-TE to combat the antimicrobial drug resistance of TB. Computer-aided drug design is a more highly valued technology than the traditional drug discovery approach. Herein, we computationally investigated a chemical dataset using QSAR models and virtually screened novel leads of imidazooxazines against the thioesterase domain, further subjecting them to molecular docking and dynamics simulation. The present study identified two molecules, 1 and 3, promising leads with minimum energy conformations of −7.63 and −7.62 kcal, respectively, providing structural insight into Pks13 inhibition. The average values of MolSA, SASA, and PSA for molecules 1 and 3 were 382.41 Å, 77.65 Å, and 195.54 Å and 386.24 Å, 71.105 Å, and 184.46 Å, respectively. In conclusion, our research has demonstrated that imidazoxazines are promising leads to combat the resistance problem of TB. Among the two potent molecules 1 and 3, molecule 1 displayed favourable interactions in the active site with good stability, as confirmed by the RMSD, RMSF, RoG, H-bond, and SASA analyses. The Molecule 1 protein complex showed two strong hydrogen bonds, effectively maintained for 80–85 % of the simulation time, indicating its stability and potency. The identified two molecules and their conformations were highly stable; hence, these findings provide valuable insight into the evolution of new therapeutic agents to address the growing problem of TB and its resistance.