INHIBITION OF BOVINE BETA-TRYPSIN, HUMAN ALPHA-THROMBIN AND PORCINE PANCREATIC BETA-KALLIKREIN-B BY BENZAMIDINE AND ITS BIS-DERIVATIVES, TRIS-DERIVATIVES AND TETRA-DERIVATIVES - THERMODYNAMIC AND MOLECULAR MODELING STUDY

The inhibitory effect of bis-, tris- and tetra-benzamidine derivatives (DAPP, TAPB and TAPP, respectively) on the catalytic properties of bovine β-trypsin (β-trypsin), human α-thrombin (α-thrombin) and porcine pancreatic β-kallikrein-B (β-kallikrein-B) was investigated (between pH 2.0 and 7.0, I= 0.1 M; T= 37.0 ± 0.5°C), and analyzed in parallel with that of benzamidine, commonly taken as a molecular inhibitor model of serine proteinases. Over the whole pH range explored, benzamidine, DAPP, TAPB and TAPP, show the same value of the association inhibition constant (K(i) M-1) for β-trypsin; at variance, the affinity of DAPP, TAPB and TAPP for α-thrombin and β-kallikrein-B is higher than that found for benzamidine association around neutrality, but tends to converge in the acidic pH limb. On lowering the pH from 5.5 to 3.0, the decrease in affinity for benzamidine binding to β-trypsin, α-thrombin and β-kallikrein-B as well as for DAPP, TAPB and TAPP association to β-trypsin reflects the a...