The determination of the thermodynamic parameters of the L-SIGN/Man84 complex formation reveals an average variation of enthalpy (DH) of -47.4 ± 1.5 kJ.mol -1 , and a variation of entropy (-TDS) of 19.5 ± 1.6 kJ.mol -1 , leading to a DG of -28 ± 0.2 kJ.mol -1 . It suggests an enthalpy driven complex formation as the major driving force, with a strong contribution to the interactions of the triazole-guanidium group added in position 2 within the L-SIGN active site. The observed entropy variation is likely due to loss of conformational freedom upon binding and solvent contribution.