The role of water molecules and its dynamics to the binding site of β-lactamase enzyme with respect to β-lactamase inhibitor

Abstract

β-lactamase hydrolyses amide bond of β-lactam ring. β-lactam antibiotics are the main arsenal in antibiotic regime.
High degree of mutation and genetic variation in β-lactamase enzymes have elevated the resistance towards β-lactamase inhibitors. There are 4 classes of β-lactamase, namely Class A, C, and D which are Serine proteases and Class B is the Metallo proteases. The most documented one is TEM, where 4 water molecules (315, 319, 440, 441) play an important role in the binding site. In the present work we have tried to explain the involvement of water molecule with respect to docking behavior with S70 (Serine), E166 (Glutamate) and N170 (Asparagine) along with an important Ω – loop (R161-D179) which allosterically modulate the behavior of the binding site. This will aid us to identify potential candidates as novel antibiotics precisely interacting with the substrate binding site and Ω – loop of β-lactamase and their interaction with these 4 water molecules. We have docked Clavulanic acid (CA), Sulbactam (SB), Tazobactam (TB) with wild (1ZG4) and mutated (1ZG6) TEM in the presence and absence of HOH, which justifies the importance of water molecules playing an important role in the hydrolysis of β-lactam as well as modulating the binding affinity of a potential drug candidate.