Comparative binding mechanisms of the reference inhibitor BIBR1532 and the Andrographis paniculata candidate LTS0004521 against telomerase

Telomerase is a critical therapeutic target in cancer, and understanding the molecular basis of ligand binding is essential for the rational design of effective inhibitors. In this study, we employed molecular dynamics simulations combined with interaction profiling and MM/GBSA energy decomposition to investigate and compare the binding mechanisms of the reference inhibitor BIBR1532 and the candidate compound LTS0004521 of Andrographis paniculata. Trajectory analysis revealed that both ligands maintained stable binding within the active site; however, they exhibited fundamentally distinct interaction patterns. BIBR1532 formed a compact and interaction-dense binding mode, dominated by strong electrostatic anchoring involving key residues such as ARG486 and ARG69, supported by persistent hydrophobic contacts. In contrast, LTS0004521 displayed a more dynamic and distributed interaction network, characterized by reduced electrostatic contributions and extensive hydrogen bonding with multiple residues, including VAL491, TYR551, GLY553, and LEU554. Per-residue energy decomposition further highlighted these differences, with BIBR1532 showing large electrostatic contributions offset by polar solvation penalties, whereas LTS0004521 exhibited a more balanced energetic profile driven by van der Waals and polar interactions across a broader residue set. Structural mapping of ligand–protein interactions confirmed that these distinct interaction strategies arise from differences in molecular architecture. Collectively, our results demonstrate that while BIBR1532 relies on localized anchoring, LTS0004521 achieves stabilization through an expanded interaction network. This shift in binding paradigm underscores the importance of interaction diversity in ligand design and provides valuable insights for the development of next-generation telomerase inhibitors with improved stability and adaptability.