Clinical Ginkgolide A-Ear-Nose-Throat (ENT) Diseases Treatment Drugs Interaction Based on the Inhibition of Phase II Drug-Metabolizing Enzymes (DMEs)

UDP-glucuronosyltransferases (UGTs) catalyze the glucuronidation of ear-nose-throat (ENT) diseases treatment drugs, and the inhibition of UGT isoforms by co-administered drugs might significantly increase the plasma exposure of drugs. This study aims to investigate the inhibition of ginkgolide A (GA) on one of the most important UGT isoforms, UGT1A1. In silico docking method was used. Chemical structure of GA was drawn using chemdraw software, and homology modeling was utilized to construct the crystal structure of UGT1A1. The chemical structure of GA can be well docked into the activity cavity of UGT1A1, and the binding free energy was calculated to be -6.41 kcal/mol. The amino acids residues in the activity cavity of UGT1A1 binding with GA contained Gly-12, Ser-13, Trp-15, Leu-16, Asp-45, Ala-47, Phe-48, Leu-51, Gln-82, Arg-83, Ser-284, Met-285, and Trp-329. Within these amino acids, the amino acids residues GLy-12, Arg-83, and Ser-284 formed hydrogen bonds with GA. For the hydrophobic interaction, the involved amino acids residues contained Ser-13, Trp-15, Leu-16, Ala-47, Phe-48, Leu-51, and Gln-82. These results showed that both hydrogen bonds and hydrophobic interaction contributed the strong inhibition of GA on the activity of UGT1A1, indicating the strong drug-drug interaction (DDI) between GA and clinical drugs mainly undergoing UGT1A1-catalyzed metabolism.