TY - JOUR T1 - Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1575 LP - 1587 DO - 10.1124/dmd.112.045823 VL - 40 IS - 8 AU - Deepak Dalvie AU - Hao Sun AU - Cathie Xiang AU - Qiyue Hu AU - Ying Jiang AU - Ping Kang Y1 - 2012/08/01 UR - http://dmd.aspetjournals.org/content/40/8/1575.abstract N2 - Current studies explored the effect of structural changes on the aldehyde oxidase (AO)-mediated metabolism of zoniporide (1). Zoniporide analogs with modifications of the acylguanidine moiety, the cyclopropyl group on the pyrazole ring, and the quinoline ring were studied for their AO-catalyzed metabolism using the human S9 fraction. Analysis of the half-lives suggested that subtle changes in the structure of 1 influenced its metabolism and that the guanidine and the quinoline moieties were prerequisites for AO-catalyzed oxidation to 2-oxozoniporide (M1). In contrast, replacement of the cyclopropyl group with other alkyl groups was tolerated. The effect of structural variation on AO properties was rationalized by docking 1 and its analogs into the human AO homology model. These studies indicated the importance of electrostatic, π-π stacking and hydrophobic interactions of the three motifs with residues in the active site. Differences in substrate properties were also rationalized by comparing their half-lives with cLogD, electrophilicity parameters [electrostatic potential (ESP) charges and energy of lowest unoccupied molecular orbitals (ELUMO)], and the energies of formation of tetrahedral intermediates (J Med Chem 50:4642–4647, 2007). Whereas the success of energetics in predicting the AO substrate properties of analogs was 87%, the predictive ability of other descriptors was none (cLogD) to 60% (ESP charges and ELUMO). Overall, the structure-metabolism relationship could be rationalized using a combination of both the energy calculations and docking studies. This combination method can be incorporated into a strategy for mitigating AO liabilities observed in the lead candidate or studying structure-metabolism relationships of other AO substrates. ER -