Friday, October 28, 2011
Hall 1-2 (San Jose Convention Center)
The structure activity relationship (SAR) of sulfonamide boronic acid inhibitors, CR14 and CR157, were compared. CR14 and CR157 were synthesized, tested in enzyme activity assays for determination of Ki values, reacted with AmpC β–Lactamase and crystallized, while bound to AmpC, using vapor distillation methods. X-ray diffraction patterns were obtained using a Synchrotron and electron density maps of each AmpC/inhibitor complex were calculated using Phenix software. Molecular replacement, refinement, ligand placement and structural analysis were done for each AmpC/inhibitor complex using Coot and Phenix softwares. CR157 had a Ki of 1.7 nM, while CR14 had a Ki of 630 nM, as determined from enzyme activity assay. The favorable Ki of CR157 is attributed by its conjugated tetrazole substituent which formed hydrogen bonds within the active site of AmpC. Conversely, CR14 had torsional strain, within the AmpC active site, due its N-methylated region which gave rise to an unfavorable of Ki.