Exploring the Natural Products Atlas (NPAtlas) Database for Hunting Prospective Irreversible Covalent DprE1...

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Computational Drug Discovery

Background:

• Tuberculosis (TB) remains a leading infectious killer globally, with rising multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains necessitating novel therapeutic strategies.
• Inhibition of decaprenylphosphoryl-D-ribose oxidase (DprE1), crucial for mycobacterial cell wall biosynthesis, presents a promising avenue for developing new anti-TB treatments.

Purpose of the Study:

• To identify and prioritize natural products from the NPAtlas database as potential covalent inhibitors of DprE1 using in silico methods.
• To screen nitro-containing natural products for their ability to inhibit DprE1, addressing the urgent need for new anti-TB therapeutics against resistant strains.

Main Methods:

• Covalent docking simulations were performed on 133 nitro-containing compounds from the NPAtlas database against the DprE1 target.
• Compounds with favorable docking scores underwent molecular dynamics simulations (MDS) and binding energy calculations using the MM-GBSA approach.
• Physicochemical properties and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiles were predicted to assess potential drug-likeness.

Main Results:

• Six NPAtlas compounds (NPA011203, NPA013234, NPA016048, NPA012944, NPA001712, NPA002823) exhibited superior binding affinities to DprE1 compared to the reference compound PBTZ169, with calculated binding free energies (ΔGbinding) ranging from -50.7 to -75.6 kcal·mol⁻¹.
• These identified compounds demonstrated stable interactions within the DprE1 active site throughout 250 ns of MDS.
• In silico predictions indicated favorable physicochemical properties, good absorption potential, and low toxicity, suggesting possible oral bioavailability.

Conclusions:

• The study successfully identified several promising natural product-derived compounds as potential covalent DprE1 inhibitors.
• These compounds represent viable candidates for further in vitro and in vivo investigation as novel anti-TB agents.
• The findings provide a strong foundation for the development of new therapeutic strategies against drug-resistant tuberculosis.