Streptomyces koyangensis L-asparaginase: computational prediction of dual-mechanism BCL-2 interaction in acute lymphoblastic leukemia.

The present research uses integrative computational analysis to assess Streptomyces koyangensis L-asparaginase as a therapeutic against acute lymphoblastic leukemia (ALL), overcoming immunogenicity and cross-reactivity issues with E. coli and Erwinia carotovora enzymes. We characterized enzyme-oncoprotein interactions using six in silico methods: homology modeling (SWISS-MODEL, AlphaFold2), molecular docking (ClusPro, HADDOCK, AutoDock Vina), 100 ns molecular dynamics (MD) (GROMACS), and pharmacophore modeling (LigandScout). Exceptional stability of the S. koyangensis-BCL-2 complex was revealed: binding energy − 13.8 kcal/mol; RMSD < 2.5 Å; Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) -68.4 ± 5.2 kcal/mol, forming a 2,145 Ų interface with 80 interacting residues. Pharmacophore modeling identified eight features targeting Asp42, Glu78, and Arg156 for rational engineering. This suggests a potential dual mechanism involving asparagine depletion and predicted BCL-2 binding interactions that may enhance leukemic apoptosis, pending experimental validation. Comparative analysis confirmed S. koyangensis demonstrated statistically significant superior binding affinity compared to alternatives (P < 0.01), offering a computational framework for identifying potential anti-cancer biotherapeutic candidates requiring experimental validation.