Melioidosis, a frequently underdiagnosed yet potentially fatal disease in the Philippines, is caused by Burkholderia pseudomallei, a pathogen noted for rapidly acquiring antibiotic resistance. The bacterial enzyme dethiobiotin synthetase (DTBS), which functions as a dimer, is an attractive drug target because of its essential role in biotin biosynthesis. In this study, computer-assisted drug discovery and development (CADDD) was employed to identify natural product inhibitors of the AlphaFold-predicted structure of B. pseudomallei DTBS using the COCONUT natural products database. A receptor cavity was mapped and used to generate a pharmacophore model for virtual screening. Phenylalanine–isoleucine–arginine tripeptide was the chemical that fit the pharmacophore the best (pharmacophore fit value 1.58). Molecular docking was used to further assess it, and the result was an interaction energy of -47.17 kJ/mol. Molecular dynamics simulation of the ligand–DTBS complex showed high stability and compactness, with low root mean square deviation and radius of gyration. Key interacting residues displayed minimal fluctuations, and the binding energy was more negative than that of reference co-crystallized DTBS homologs. Short-range interaction energies from Lennard-Jones and Coulombic potentials were –91.17 ± 5.0 kJ/mol and –195.28 ± 7.7 kJ/mol, respectively. The findings point to thermodynamically advantageous binding and the possibility that the top ligand could block DTBS by altering its active dimeric structure, offering a promising avenue for the creation of new anti-melioidosis drugs.
