Computer aided drug design strategies for the development of novel beta lactam analogs targeting penicillin binding proteins

Computers and computational methods are indispensable tools in modern drug discovery pipeline. Early lead identification and lead optimization are the present day goals of drug discovery. Antibiotics like penicillin and cephalosporin containing beta lactam ring system are the dominant class of agents currently used for the chemotherapy of bacterial infections. In this present study we have used an approach combing molecular docking and QSAR analyses on a series of compounds called Imidazetines, a novel beta lactam analog known to possess antibacterial activity. X-ray crystallographic studies reveal that beta lactam compounds have affinity for Penicillin Binding Proteins (PBP) and hence known 3D structure of PBP (pdb code: 1CEF) was used as macromolecular target. Molecular modeling studies were performed on Silicon Graphics work stations using Insight II. The novel ligands were docked in to the binding pocket and the results of the docking studies revealed that these novel ligands are able to occupy the same binding pocket with better interactions. The stability of the complex are maintained by several hydrogen bonding interactions. The key amino acid residues involved in ligand binding were found to be conserved among other homologous of PBP. QSAR analyses were performed on these compounds and ADME/T properties were predicted based on the first generation Lipinski´s Rule of Five. The results obtained from our study could further the design of new molecules with promising activity in the future.