Acetohydroxyacid Synthase (AHAS) Inhibitors as Antitubercular Agents: Insights From Molecular Docking and Dynamics Simulations.

Abstract

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 4 compounds (with docking score above -8.2 kcal/mol) resulting from the docking studies were subjected to rigorous molecular dynamics simulations, spanning a runtime of 100 ns, to assess their stability across various parameters including root mean square deviation (RMSD), root mean square fluctuation (RMSF), secondary structure elements (SSEs), radius of gyration (rGyr), 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 containing heterocyclic rings (1,3,5-triazine/imidazole) are essential to have the potential binding interactions with the AHAS enzyme. Some of the interactions were persisted for more than 75% of the simulated time, which shows the strength of the interactions. The findings suggest these lead molecules as promising candidates for AHAS inhibition, a potential avenue for TB treatment and management.