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

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Drug Design

Background:

• Acetohydroxyacid synthase (AHAS) is essential for Mycobacterium tuberculosis growth, making it a key target for tuberculosis (TB) drug development.
• Structure-based drug design (SBDD) offers a rational approach to identify novel inhibitors for essential bacterial enzymes.

Purpose of the Study:

• To design and evaluate novel compounds as potential inhibitors of Mycobacterium tuberculosis AHAS.
• To identify lead compounds with favorable binding interactions and stability for further drug development against TB.

Main Methods:

• Designed 160 novel compounds using SBDD principles.
• Performed molecular docking and 100 ns molecular dynamics simulations (RMSD, RMSF, rGyr, SASA, MM-GBSA) to assess binding and stability.
• Analyzed molecular interactions, focusing on key heterocyclic ring contributions.

Main Results:

• Top 4 compounds identified via docking (score > -8.2 kcal/mol).
• Compounds KG 98 and KG 131 showed superior stability during molecular dynamics simulations.
• Nitrogen-containing heterocyclic rings (1,3,5-triazine/imidazole) were crucial for sustained binding interactions (>75% simulation time).

Conclusions:

• Compounds KG 98 and KG 131 are promising lead molecules for AHAS inhibition.
• These findings support AHAS as a viable drug target for developing new anti-TB therapeutics.
• The study highlights the importance of specific heterocyclic scaffolds for effective enzyme inhibition.