Anti - Gram - Negative Bacteria Deacetylase LpxC Inhibitor Design

Structure-based dryg design(SBDD) is a sufficient strategy applied in drug discovery. Served as a powerful computer-aided drug design approach, pharmacophore generation methods and docking methods have been wildly used for searching leading compounds. 3D QSAR Pharmacophore Generation and docking methods were attempted to design noval inhibitors against UDP-3-O-(R-3-hyrdoxymyristoyl)-N-acetyl glucosamine(LpxC).LpxC plays as an essential component in the biosynthetic of lipopolysaccharide coat of P.aeruginosa and other Gram negative bacteria, a zinc dependent deacetylase. New scaffold LxpC inhibitors are required urgently in view of poorly druggability of LpxC inhibitors reported. In this work, we expatiate the application of structure based virtual screening methods in LxpC inhibitors design. 3D QSAR Pharmacophores of LpxC inhibitors were built using Discovery Studio3.0 with a training set consisted of 18 LpxC inhibitors reported, in which hypothesis1 showed considerable qualities of both predictability and confidence as a most pharmacophore. High scored compounds were gained through a screening by SPECS database, hypothesis1 filtered, then further docked into active site of a LpxC crystal structure where 15 compounds of the highest score were obtained based on PLP1 scoring function, led to improved novel drug design for LpxC inhibitors against Gram negatives.