Exploring Small Molecules as Novel Drug Candidates Targeting 4-Hydroxy-Tetrahydrodipicolinate Reductase in Mycobacterium tuberculosis: Insights from Molecular Dynamics Simulation and Principal Component Analysis

• Published in: Letters in Applied NanoBioScience Vol. 14; no. 1; p. 2
• Format: Journal Article
• Language: English
• Published: 30.03.2025
• ISSN: 2284-6808; 2284-6808
• DOI: 10.33263/LIANBS141.002

4-hydroxy-tetrahydrodipicolinate reductase (DapB) is a vital enzyme present in bacteria, primarily Mycobacterium tuberculosis, and plays a pivotal role in the biosynthesis of diaminopimelic acid (DAP), an essential component of the bacterial cell wall. Inhibition of DapB disrupts DAP synthesis, leading to structural damage to the bacterial cell wall, making the bacterium more susceptible to the host immune response, and enhancing the effectiveness of existing anti-TB treatments. DapB is absent in human cells, which makes it a suitable pharmacological target. This study utilized advanced computational techniques, including structure-based virtual screening (SBVS), ADMET profiling, molecular docking, dynamic simulations, and principal component analysis, to identify small molecules from the vast digital library of the MCULE database that selectively inhibits DapB as a strategy to combat tuberculosis, a significant global health challenge. The proposed research identified MCULE-9296301908-0-1, with a computed binding energy (ΔG) of -9.9 kcal/mol, as a promising candidate for an anti-tubercular drug. Notably, this compound surpassed the binding affinity of a known potential inhibitor, 2,6-Pyridinedicarboxylic acid (PDC) (-7.5 kcal/mol). However, research findings depend on computational methods, and rigorous laboratory experiments are necessary for validation. This study represents a significant step toward the fight against tuberculosis drug resistance.