New Delhi metallo-beta-Lactamase

New Delhi metallo-beta-lactamase-1 (NDM-1) is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics including Carbapenem family. Carbapenems are a class of beta-lactam antibiotics that are capable of killing antibiotic resistant bacteria by inhibiting the synthesis of one of their cell wall layers . Bacteria that produce carbapenemases are often referred as "superbugs" because infections caused by them are difficult to treat .

CARBAPENEM BACKBONE

NDM-1 was first detected in a Klebsiella pneumoniae isolate from a Swedish patient of Indian origin in 2008.

The most common bacteria that make this enzyme are Gram-negative such as Escherichia coli and Klebsiella pneumoniae. The gene for NDM-1 can easily spread from one strain of bacteria to another by horizontal gene transfer.
Such bacteria are usually susceptible to polymyxins and tigecycline.

 Polymyxins

and Tigecycline are two antibioics that can be used for treating infections caused by NDM-1. But they both are also not quite effective sometimes. Polymyxins are toxic in nature. They are chosen as the last option if no other drug is working.

Also

And

Tigecycline is an expensive drug, so it is not in the reach of everybody.

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its name suggests, the enzyme is always coupled with a metal ion(usually Zn). of the structures of NDM-1 from different bacteria are modeled and are submitted in the PDB. enzyme structures from many other bacteria are yet to be modeled. These include E.coli, Acinetobacter baumannii etc.

Some

Although

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the NDM-1 gene spreads by horizontal gene transfer, the structure would be the same. of Blast against PDB reveals that the sequence of NDM-1 from E.coli has a strong structural similarity with the other modeled structures of it. the new structure of NDM-1 can be easily modeled using Homology Modeling.

Result

So

The structure having least RMSD value will be selected for the study.

The generated model can be verified using PROCHECK, PROSA, Verify3d servers.
This may provide information about the quality of modeled structure. Active site of the modeled structure can be identified using various web services e.g. PDBsum, LigSite, 3dLigandSite, Depth etc.

Some of the structures in PDB are modeled along with their inhibitors and ligands such as GOL,ZZ7,M5P etc. These ligands can be used for similarity searching in various databases as Pubchem, chEMBL, ZINC etc. The best resulting structures of this similarity search could be taken for docking with the modeled structure.
Other then these structures, Tigecycline, the effective antibiotic over NDM-1, can also be used for similarity searching.

 The

results could be further refined on the basis of Lipinskis rules and ADMET prediction. would result in a fewer no. of ligands, which can be docked with our modeled structure.
Docking results could help in identifying a potential structure, that can be developed as a drug.

This

Final