Figure 8.

Michaelis−Menten complexes of vaborbactam in the sp2 configuration shown in multiple different poses obtained upon docking into the active sites of KPC-2 (PDB 2OV5) and PenA1 (PDB 3W4Q). (a) Within KPC-2, several docked vaborbactam molecules (yellow) formed favorable complexes. The surface of the active site was colored by hydrogen-bonding type with hydrogen donors colored in magenta and hydrogen acceptors in green. The surface further reveals the difference in the active site sizes between the two enzymes with the KPC-2 active site being narrower than that of PenA1. (b) A close up of the active site interactions in KPC-2 with a single selected vaborbactam pose obtained from docking reveals favorable interactions with the boronate near S70 (<2 Å) and stacking interactions between W105 (cyan) and cyclic boronate moiety. Hydrogen bonds are represented by dashed green lines; stronger hydrogen bonding interactions (e.g., ionic interactions) are in orange dashed lines. (c) Conversely, with PenA1, the multiple poses of vaborbactam (cyan) obtained from the docking formed mostly unfavorable interactions that were driven by larger active site of PenA1. Surface representations are the same as described in panel (a) for KPC-2. (d) A close up of the PenA1 active site with a single selected vaborbactam pose obtained from docking reveals that the carboxylate moiety of vaborbactam competes for binding to K234 and T235, thus moving the boronate away from S70 (>4 Å); the faint orange arrow points out the distance between hydroxide side chain of S70 and the boronate moiety. Moreover, during docking two conformations of Y105 (pink/yellow) were observed that competed for interactions with cyclic boronate moiety and the thiophene ring of vaborbactam. The hydrogen bonding interactions are the same as described in panel (b) for KPC-2.