Covalent docking of selected boron-based serine beta-lactamase inhibitors

AmpC beta-lactamase is a hydrolytic enzyme conferring resistance to
beta-lactam antibiotics in multiple Gram-negative bacteria. Therefore,
identification of non-beta-lactam compounds able to inhibit the enzyme
is crucial for the development of novel antibacterial therapies. In
general, AmpC inhibitors have to engage the highly solvent-exposed
catalytic site of the enzyme. Therefore, understanding the implications
of ligand-protein induced-fit and water-mediated interactions behind the
inhibitor-enzyme recognition process is fundamental for undertaking
structure-based drug design process. Here, we focus on boronic acids, a
promising class of beta-lactamase covalent inhibitors. First, we
optimized a docking protocol able to reproduce the experimentally
determined binding mode of AmpC inhibitors bearing a boronic group. This
goal was pursued (1) performing rigid and flexible docking calculations
aiming to establish the role of the side chain conformations; and (2)
investigating the role of specific water molecules in shaping the enzyme
active site and mediating ligand protein interactions. Our calculations
showed that some water molecules, conserved in the majority of the
considered X-ray structures, are needed to correctly predict the binding
pose of known covalent AmpC inhibitors. On this basis, we formalized our
findings in a docking and scoring protocol that could be useful for the
structure-based design of new boronic acid AmpC inhibitors.