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Abstract
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.
| Abbreviations | ||
| ADME | = | Absorption, Distribution, Metabolism and Excretion |
| BBB | = | Blood brain barrier |
| CHARMM | = | Chemistry at Harvard Macromolecular Mechanics |
| COM | = | Center of Mass |
| CYP2D6 | = | Cytochrome P450 2D6 |
| DS | = | Discovery Studio |
| ESBL | = | Extended Spectrum Beta-lactamases |
| FDA | = | Food and Drug Administration |
| GLASS | = | Global antimicrobial resistance surveillance system |
| GROMACS | = | GROningen MAchine for Chemical Simulations |
| KDE | = | Kernel Density Estimation Plots |
| MBL | = | Metallo-beta-lactamase |
| MBL-C | = | Metallo-beta-lactamase bound to L-Captopril |
| MBL-E | = | Metallo-beta -lactamase bound to Eupalitin |
| MBL-I | = | Metallo-beta -lactamase bound to Imipenem |
| MBL-L | = | Metallo-beta -lactamase bound to Luteolin |
| MBL-R | = | Metallo-beta -lactamase bound to Rosmarinic acid |
| MD | = | Molecular Dynamics |
| MMPBSA | = | Molecular Mechanics Poisson − Boltzmann surface area |
| NPT | = | Number of atoms in the system, Pressure of the system and Temperature of the system |
| ns | = | Nano seconds |
| NVT | = | Number of atoms in the system, Volume of the system, and Temperature of the system |
| PDB | = | Protein Data Bank |
| Rg | = | Radius of Gyration |
| RMSD | = | Root Mean Square Deviation |
| RMSF | = | Root Mean Square Fluctuation |
| SASA | = | Solvent Accessible Surface Area |
| SPC/E | = | Simple Point Charge |
| WHO | = | World Health Organization |
Communicated by Ramaswamy H. Sarma
Acknowledgments
We thank the Management and Principal of M.S. Ramaiah Institute of Technology, Bengaluru, India and Siddaganga Institute of Technology, Tumakuru, India, for their encouragement and support. We, also thank Karnataka Biotechnology and Information Technology Services (KBITS), Bangalore for providing the grant to establish the computational facility under Biotech Policy-II, Biotechnology Finishing School and Biotechnology Skill Enhancement Programme (BiSEP) at the Department of Biotechnology, Siddaganga Institute of Technology, Tumakuru-572103, Karnataka. We thank Mr. Naveen Kumar N, Faculty, BiSEP Department of Biotechnology, Siddaganga Institute of Technology, Tumakuru for sharing the R-code to plot the graph and Dr. M. G. Gautham, Assistant Professor, Department of Mechanical Engineering, Siddaganga Institute of Technology, Tumakuru for his assistance in drawing the Figure with Solid Edge software.
Disclosure statement
The authors declare that they have no conflict of interest.