Exploring phytochemicals and marine natural products as alternative therapeutic agents targeting phosphotransacetylase (PTA) in Mycobacterium tuberculosis: An underexplored drug target

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a significant global health threat due to its widespread prevalence and increasing drug resistance. This study targets phosphotransacetylase (PTA), an essential enzyme in acetate metabolism, as a potential therapeutic target. A comprehensive multi-tiered virtual screening approach was employed to identify potent phytochemicals and marine natural products (MNPs) from five databases (AMMPDB, CMNPD, MNPD, Seaweed and SPECS). Five promising bioactive molecules (AMMPDB10473, CMNPD23347, CMNPD5918, MNPD6660, and SPECS-AK-693) were identified, showing high docking scores (-8.17 to -10.83 kcal/mol) and MM-GBSA binding energy scores (-47.51 to -59.14 kcal/mol). These molecules adhered to Lipinski's rule of five (Ro5) and demonstrated acceptable pharmacokinetic profiles. Density functional theory (DFT) calculations further validated the interaction potential of these molecules through HOMO and LUMO analysis. Long-range molecular dynamics simulations (MDS) over 300 ns confirmed the structural stability and enhanced hydrogen-bonding potential of the natural products-PTA complexes. Principal component analysis (PCA) and free energy landscape (FEL) contour plots revealed a single dominant energy basin, indicating structural stability and limited conformational flexibility of the complexes. Additionally, MMPBSA analysis corroborated the strong binding affinities of the identified hit molecules with PTA. Critical 'hot spot' residues (Phe516, Cys530, Ala531, and Tyr639) were identified, contributing significantly to the structural stability and binding energy of the complexes. This computational study offers valuable insights into the potential of these lead molecules for combating TB, providing a foundation for experimental validation and innovative therapeutic development, and paving the way for future research and breakthroughs in TB treatment.