Structural insights into ?-glucuronidase inhibition to mitigate camptothecin chemoterapeutics side effects

Abstract

Selective Escherichia coli ?-glucuronidase (eGUS) inhibitors, which do not affect human ?-glucuronidase (hGUS), greatly alleviate side effects (severe diarrhea) of worldwide used chemotherapeutics, camptothecin and its derivatives. We have studied the probable mechanism of the selectivity of eGUS inhibition. Structural superposition has shown high structural homology in tertiary structure of hGUS and eGUS. Active center models of the enzymes have been build, and the principal difference in quaternary structure of the two enzymes has been found. The four active centers of the human enzyme are positioned separately, each in the area of its own polypeptide chain; their amino acids are positioned distantly from those of the neighboring subunits. In contrast, each eGUS active center includes Phe365 amino acid residue derived from a neighboring polypeptide chain. The improved model of eGUS subunit substrate binding site suggests that future eGUS molecular docking and structure based in silico virtual screening studies should be performed with the dimeric structure rather than with a single subunit. All presently known natural eGUS inhibitors have been characterized, the possibility and expediency of obtaining of such inhibitors from herbal sources has been justified. The part of the research is aimed to advance towards green technologies in pharmaceutics.