Design and modeling studies on isoindole derivatives as a novel non-classical Anti bacterial agents

Abstract

Isoindole antibacterial agents are currently used for treatment of various bacterial infections. The isoindoles are compounds of intense interest because of their inhibitory effect on Histidinol dehydrogenase enzyme. The invention provides histidinol dehydrogenase polypeptides and DNA (RNA) encoding histidinol dehydrogenase polypeptides and methods for producing such polypeptides by recombinant techniques. Also provided are methods for utilizing histidinol dehydrogenase polypeptides to screen for antibacterial compounds. Histidinol dehydrogenase (HDH) is one of the enzymes involved in the L-histidine biosynthesis pathway. HDH is a dimer that contains one Zn ion in each identical subunit. In this study, we designed isoindole agents as a novel histidinol dehydrogenase inhibitor .Then predicted possible binding conformation of our agents, which is experimentally not known, using a computational modeling method. Conformations of the designed compounds were optimized through semi-empirical method followed by PM3 calculation by the program HYPERCHEM. Among all energy minima conformers, the global minimum was selected and the QSAR properties was obtained. Then the crystal of L-histidinol dehydrogenase was obtained from the Protein Data Bank(PDB) server. Finally Docking calculations were carried out using Auto-Dock program. The good interaction of our isoindole derivatives showed that they can be as possible anti bacterial agents.