An explorative study on potent gram-negative specific LpxC inhibitors using molecular docking and molecular modeling

Pathogenic Gram-negative bacteria, including Pseudomonas aeruginosa and Escherichia coli areresponsible for nearly half of the serious human infections and sepsis is a common complication fromGram-negative. Therefore, there is already an urgent need for identification and development of novelantibiotics particularly those effective for the treatment of Gram-negative bacterial infections. Gramnegativebacteria hasouter membrane containing lipopolysaccharides (LPS) which consists of lipid A inits outer leaflet. Lipid A is necessary to protect Gram-negative bacteria against external agents such asantibiotics and detergents. The unique and essential zinc-dependent metalloamidase UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), which catalyzes the committed step of lipidA biosynthesis, has emerged as an attractive antibiotic target.CoMFA, CoMSIA, HQSAR, moleculardocking and in silico ADMET prediction have been performed for LpxC inhibitors. This study has beencarried out to determine the binding mode and drug likeliness nature of compounds.CoMFA, CoMSIA,HQSAR models were generated using 32 compounds. The generated models were found to be statisticallysignificant as CoMFA model had (R2=0.967, Q2=0.804, R2PRED=0.827); CoMSIA model had (R2=0.963,Q2=0.752 R2PRED=0.857)andHQSARmodel had (R2=0.969 Q2=0.937 R2PRED=0.892). In order toevaluate the effectiveness of the docking protocol, co-crystallized ligand was extracted from the ligandbinding domain of the protein and was re-docked into the same position. The conformer obtained on redockingand the co-crystallized ligand were superimposed and the root mean square deviation betweenthe two was found to be 1.21 Å. Outcomes of this study provide an insight for designing novel LpxCinhibitors.

کلیدواژه ها:

gram-negative specific LpxC inhibitors ، CoMFA ، CoMSIA ، HQSAR ، molecular docking