Structural specificity requierements in the binding of beta lactam antibiotics to human serum albumin
NERLI, BIBIANA; ROMANINI, DIANA; PICÓ, GUILLERMO
Lugar: Estocolmo; Año: 1997 vol. 104 p. 179 - 202
Abstract The binding of some cephalosporins of pharmacological interest, to human serum albumin was studied using ultrafiltration method. The identification of the binding sites in albumin was also performed using probes for the so-called sites I, II, bilirubin and fatty acids binding sites. Cephalosporins were classified into three groups according to their affinity for albumin: low affinity (K= 10-102 M-1), medium affinity (K=103 M-1) and high affinity (K=104M-1). Cephalosporin binding to albumin produced a perturbation of several basic aminoacids of the protein such as histidine and lysine. It was found that only cefuroxime, ceftazidime and cefoperazone interact slightly with site I on serum albumin, while site II possesses capacity to bind: cephradine, cephalexin, ceftazidime, ceftriaxone, cefoperazone, cefaclor and cefsulodin. The bilirubin binding site showed capacity to interact with a great number of cephalosporins: ceftriaxone, cefazolin, cephaloglycin, cefamandole, cefotaxime, cefoxitin, cefuroxime, cefoperazone and cefadroxil. Ceftriaxone showed capacity to bind to the fatty acid binding site on HSA. No relation was found between the displacement of the marker and the chemical nature of the substituents at R1 and R2. Cephalosporins interact with HSA at the binding region that involves: tyrosyl 411, histidyl 146 and lysyls 195, 199, 225, 240 and 525 residues. The chemical modification of specific aminoacids showed that the interaction of these aminoacids with beta lactam antibiotics is not carried out to the same extent for all the cephalosporins tested. The results obtained revealed that the binding sites for cephalosporins on albumin are structurally heterogeneous, having different aminoacids in the vicinity of the ligand molecule.