Multi-scale computational modeling to identify novel chemical scaffolds as trehalose-6-phosphate phosphatase inhibitors to combat .

Unlabelled: causes melioidosis, a deadly infection having high fatality rates (20-50%) and antibiotic resistance, however, there's no effective drug or vaccine available. Trehalose is a vital sugar for which influences the pathogen resilience and pathogenicity. This proposed computational strategy focuses on developing novel drugs against Trehalose-6-phosphate Phosphatase (TPP) to combat infections. This study found three novel drugs from Asinex, Zinc, Chembridge, and Drugbank databases through a comprehensive structure-based virtual screening. The process screened the top three compounds: BDG_34042863, BDF_33738612, and DB00139 along with control (2-methyl-6-phenoxytetrahydro-2 H-pyran-3,4,5-triol) with a binding energy score of -8.8 kcal/mol, -8.4 kcal/mol, and - 7.7 kcal/mol, -6.4 kcal/mol respectively. In a molecular dynamics simulation, the Ligand-protein complexes demonstrated substantial non-covalent interactions as well as a stable docked intermolecular binding conformation. Throughout the MDS (molecular dynamic simulation) period, the studied compounds showed stable consistent interactions; there were no noticeable changes in the interactions or binding mode. The BDG_34042863, BDF_33738612, and DB00139 had a mean deviation of 4.04, 7.18, and 7.10 measured in Å, respectively. In addition, the simulation trajectories of complexes underwent MM/GBSA analysis, which revealed binding affinity scores of -33.39, -41.1, -49.16, and - 41.29 measured in kcal/mol for the control, BDG_34042863, BDF_33738612, and DB00139, respectively. According to DFT Analysis, BDF_33738612 showed the smallest energy gap (0.46 eV), indicating high reactivity, while DB00139 showed the largest energy gap (5.66 eV), illustrating good kinetic stability compared to the control. The compounds exhibit notable differences in reactivity and stability levels as their HOMO-1 to LUMO + 1 and HOMO-2 to LUMO + 2 orbitals have greater energy gaps, ranging from 5.06 eV to 6.69 eV and 5.66 eV to 7.09 eV, respectively. The compounds also had favorable pharmacokinetic characteristics and were categorized as druglike. Among the selected compounds, BDF_33738612 demonstrated the most promising findings followed by BDG_34042863 and DB00139. The compounds may be employed in an experimental study to examine their anti-TPP activity against .

Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00309-5.