DFT Design of Inhibitors of the LpxC Enzyme

Abstract

In recent years bacterial infections have become more resistant to treatments, posing a challenge for both researchers and health professionals. It has become imperative that novel, effective therapies against these resistant bacterial infections be discovered. Gram-negative bacteria present an additional challenge due to the presence of a selectively permeable outer membrane. Among the components of the outer membrane is Lipid A, which is responsible for the growth and pathogenicity of Gram-negative bacteria. The enzyme LpxC, a zinc-dependent deacetylase, is responsible for catalyzing the first committed step in the biosynthetic pathway of Lipid A. The inhibition of LpxC would therefore, prevent the production of Lipid A, and hence result in a corrupted outer membrane. Starting from an LpxC crystal structure with a natural substrate bound in the active site, we have designed and optimized the position of several novel ligands in the active site. The structure for these ligand-protein complexes were optimized using M06l and the 6-31G basis set both in vacuo and in solution phase. Interaction energies for the ligand and protein complex were calculated using M06l with the 6-311+G* basis set. Desolvation and simplified zinc binding studies have also been performed to confirm that our model chemistry describes the zinc binding in the protein appropriately. Additionally, Log P and Log D have been computationally calculated to determine whether the molecules may be biologically active. Initial work shows several promising candidates for the inhibition of LpxC.