Structure based design of an in vivo active hydroxamic acid inhibitor of P. aeruginosa LpxC

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• 作者：Joseph S. Warmus^a ; ^{Joseph.Warmus@Pfizer.com} ; Cheryl L. Quinn^b ; Clarke Taylor^a ; Sean T. Murphy^a ; Timothy A. Johnson^a ; Chris Limberakis^a ; Daniel Ortwine^a ; Joel Bronstein^b ; Paul Pagano^b ; John D. Knafels^c ; Sandra Lightle^c ; Igor Mochalkin^c ; Roger Brideau^b ; Terry Podoll^d
• 关键词：LpxC ; Antibacterial ; Gram negative ; Structure based drug design ; Hydroxamic acid ; Pseudomonas aeruginosa ; LipE ; Lipophilic efficiency ; Computer aided drug design
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 April, 2012
• 卷：22
• 期：7
• 页码：2536-2543
• 文件大小：2225 K

摘要

Lipid A is an essential component of the Gram negative outer membrane, which protects the bacterium from attack of many antibiotics. The Lipid A biosynthesis pathway is essential for Gram negative bacterial growth and is unique to these bacteria. The first committed step in Lipid A biosynthesis is catalysis by LpxC, a zinc dependent deacetylase. We show the design of an LpxC inhibitor utilizing a robust model which directed efficient design of picomolar inhibitors. Analysis of physiochemical properties drove design to focus on an optimal lipophilicity profile. Further structure based design took advantage of a conserved water network over the active site, and with the optimal lipophilicity profile, led to an improved LpxC inhibitor with in vivo activity against wild type Pseudomonas aeruginosa.