Potential Inhibitors of Mycobacterium abscessus VapC5 Protein: A Molecular Dynamics Simulation Study

Mycobacterium abscessus (MAB) is severely resistant to available antibacterial agents. The current study aimed to find natural inhibitors against MAB to fight the resistant isolates.

Ten lead compounds were selected against MAB VapC5 for Molecular Dynamics (MD) simulations for 200 ns. Root Mean Square Fluctuation (RMSF), Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), and Dynamic Cross Correlation Matrix (DCCM) of apo and VapC5-ligand complexes were analyzed.

Among the ten lead compounds, eight compounds (deoxy artemisinin, glaucocalyxin A, (1R,4E,9E,11S)-4,12,12-trimethyl-8-oxobicyclo[9.1.0]dodeca-4,9-dien-2-yl acetate, isorhamnetin, Kissoone C, piperlongumine, tectorigenin, and wogonin) showed a good potential against MAB VapC5. The apo-VapC5 exhibits a stable RMSD of 0.154 nm and RMSF of 0.088 nm ± 0.14. At the same time, ligands including Deoxy Artemisinin, Ftaxilide, Glaucocalyxin-A, and others range in RMSF from 0.097 nm to 0.147 nm, with standard deviations varying between 0.12 and 0.22. The highest RMSF was observed with Kissoone C (0.147 nm ± 0.15), and the lowest with Tectorigenin (0.097 nm ± 0.12). The Apo-VapC5 exhibited an Rg of 3.064 nm, whereas in complexes with ligands, the Rg values ranged from 0.097 nm to 0.147 nm. The DCCM analysis of VapC5-ligand complexes also reveals a more pronounced negative correlated motion.

The simulation outcomes indicate that ligand binding enhanced the structural stability of VapC5 compared to the apo form. Among the tested compounds, deoxy artemisinin, glaucocalyxin A, and tectorigenin showed the most stable interactions, highlighting their potential as promising VapC5 inhibitors.

The selected compounds exhibit good binding affinity and residue interaction patterns. The ligand binding influenced VapC5 flexibility and conformational changes observed in complexes with MABVapC5, which could be useful inhibitors after experimental validation.