Paul Erdman - Discovery of Antibacterial Biotin Carboxylase Inhibitors by Virtual Screening and Fragment-Based Approaches

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      Publication Details (including relevant citation   information):

      ACS Chem. Biol., 2009, 4 (6), pp 473–483


      Abstract Image

      As part of our effort to inhibit bacterial fatty acid   biosynthesis through the recently validated target biotin   carboxylase, we employed a unique combination of two emergent   lead discovery strategies. We used both de novo  fragment-based drug discovery and virtual screening, which   employs 3D shape and electrostatic property similarity searching.   We screened a collection of unbiased low-molecular-weight   molecules and identified a structurally diverse collection of   weak-binding but ligand-efficient fragments as potential building   blocks for biotin carboxylase ATP-competitive inhibitors. Through   iterative cycles of structure-based drug design relying on   successive fragment costructures, we improved the potency of the   initial hits by up to 3000-fold while maintaining their   ligand-efficiency and desirable physicochemical properties. In   one example, hit-expansion efforts resulted in a series of   amino-oxazoles with antibacterial activity. These results   successfully demonstrate that virtual screening approaches can   substantially augment fragment-based screening approaches to   identify novel antibacterial agents.

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