Structural insights of metallo-beta-lactamase revealed an effective way of inhibition of enzyme by natural inhibitors

Metallo-beta-lactamase (MBL) is a class of enzyme that catalyzes the hydrolysis of a broad range of beta-lactam antibiotics leading to the development of drug resistance in bacteria. Inhibition of MBL is therefore pursued as a potential way to increase the susceptibility of bacteria to beta-lactam antibiotics. In this study, MBL inhibitors from natural sources such as Eupalitin, Rosmarinic acid and Luteolin are used as a potential alternative to explore their effect. The crystal structure of MBL revealed a hydrolyzed Meropenem, which was undocked from the active center pocket to get the apo-protein. The apo-protein was re-docked with substrate, three known MBL inhibitors and natural compounds to prepare the starting structure in the current work and to draw conclusions. Further, to explore the efficiency of natural inhibitors, we analyzed the dynamic behavior of the enzyme over simulation time using molecular dynamics studies. Our results suggest that MBL enzyme adopted altered conformational state in the presence of natural inhibitor. This is because, the natural inhibitors were tried to occupy a different binding pocket in the enzyme by causing positional drift from the active center pocket. Here, the different binding pocket partly comprised of active site pocket and partly by a new region explored by ligand, making it inappropriate for substrate to occupy the active site. Thus natural inhibitors may be potential entities to target MBL.