MOLECULAR ARCHITECTURE OF SAXITOXIN-LACTOFERRIN INTERACTIONS: STRUCTURAL REFINEMENT AND BIOLOGICAL IMPLICATIONS

Saxitoxin (STX) is a highly potent, naturally occurring alkaloid neurotoxin produced by marine dinoflagellates and cyanobacteria, recognized as the primary causative agent of paralytic shellfish poisoning (PSP). By selectively and reversibly blocking voltage-gated sodium channels (Nav), it disrupts neuromuscular transmission. This work investigates the molecular properties and interaction patterns of saxitoxin derivatives using structural bioinformatics, aiming to evaluate their pharmacological, toxicological, and biosafety potential. Human lactoferrin (PDB ID: 1LFG) was selected as the molecular target due to its structural similarity to saxiphilin, a known saxitoxin-binding protein. We utilized AutoDock Vina and the DockThor server to analyze the binding of saxitoxin and its analogs to this protein. In the molecular docking analysis, the analogs GTX2 and C1 were simulated with tyrosine (Tyr) residues Tyr192 and Tyr528 in both AutoDock Vina and DockThor. GTX2 yielded a binding affinity of −9.1 kcal/mol in AutoDock Vina with Tyr192 and −8.3 kcal/mol in DockThor, as well as −7.9 kcal/mol in AutoDock Vina with Tyr528 and −8.3 kcal/mol in DockThor. Analog C1 yielded −9.7 kcal/mol in AutoDock Vina with Tyr192 and −8.3 kcal/mol in DockThor, along with −9.9 kcal/mol in AutoDock Vina with Tyr528 and −8.3 kcal/mol in DockThor. Both analogs interacted with the residues PRO (proline), ASN (asparagine), and GLN (glutamine), all located on chain A of lactoferrin. Furthermore, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling and target prediction tools, such as the Deep-PK and ProTox 3.0 web servers, will be applied to comprehensively assess the biopharmaceutical profiles of these analogs. Additionally, these interactions will be validated through molecular dynamics simulations.

This work was supported by the Coordination for the Improvement of Higher Education Personnel (CAPES) and by the Army Biology Institute (IBEX).