Structure-Based Virtual Screening of Natural Product-Derived Inhibitors Targeting Rv3806c in the Decaprenylphosphoryl-d-Arabinose Biosynthetic Pathway of Mycobacterium tuberculosis

Phosphoribosyl transferase (Rv3806c) is a key enzyme in Mycobacterium tuberculosis. It is involved in the biosynthesis of decaprenylphosphoryl arabinofuranose, which is the sole donor of arabinofuranose residues in the biosynthesis of arabinogalactan and lipoarabinomannan. Inhibition of Rv3806c disrupts cell wall assembly, making it an attractive target for anti-tuberculosis drug development. In this study, a structure-based computational approach was employed to find natural inhibitors of Rv3806c. In silico ADMET filtration of 36,530 compounds from the Natural Products Atlas (NPAtlas) database and 105,909 compounds from the Bioactivity of Indian Medicinal Plants (BIMP) database yielded 285 and 553 compounds, respectively. Molecular docking analysis identified four compounds (NPA004179, NPA011911, BIMP003941, and BIMP004391) with binding affinities (−8.2, −7.5, −7.8, and −8.6 kcal/mol), respectively, stronger than the binding affinity of the native ligand (−7.2 kcal/mol). Molecular dynamics simulations demonstrated that all complexes exhibited low structural deviation, consistent hydrogen bonding, and stable protein–ligand compactness throughout the simulation period. MMPBSA analysis revealed thermodynamic stability of the Rv3806c–ligand complexes with binding energies ranging from (–14.91 to –26.30 kcal/mol). These computational findings may serve as a useful starting point for further optimization and experimental validation towards anti-tuberculosis therapeutics targeting Rv3806c.