Acetohydroxyacid Synthase (AHAS) inhibitors as Antitubercular agents: Insights from Molecular Docking and Dynamics Simulations.

Acetohydroxyacid synthase (AHAS) is a vital enzyme in Mycobacterium tuberculosis, the pathogen causing tuberculosis (TB), involved in branched-chain amino acid synthesis. Targeting AHAS for drug design against TB offers a promising strategy due to its essentiality in bacterial growth. In current investigation, we have designed 160 novel compounds by leveraging key scaffolds identified through structure-based drug design (SBDD) methodologies. Subsequently, these compounds underwent molecular docking analysis to elucidate their potential interactions with the AHAS protein. The top four compounds resulting from the docking studies were subjected to rigorous molecular dynamics simulations, spanning a runtime of 100 nanoseconds, to assess their stability across various parameters including Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Secondary Structure Elements (SSE), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and MM-GBSA free energy values. Remarkably, compounds KG 98 and KG 131 exhibited superior stability profiles across all analyzed parameters. From the detailed interactions analysis, it was found that the nitrogen containg heterocyclic rings (1,3,5-triazine/imidizole) are essential to have the potential binding interactions with the AHAS enzyme. The findings suggest these lead molecules as promising candidates for AHAS inhibition, a potential avenue for tuberculosis treatment and management.