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An Ultraefficient Affinity-Based High-Throughout Screening Process: Application to Bacterial Cell Wall Biosynthesis Enzyme MurF
1 Department of Target and Lead Discovery, Global Pharmaceutical R&D, Abbott Laboratories, Abbott Park, Illinois
* To whom correspondence should be addressed. E-mail: kenneth.m.comess{at}abbott.com.
The authors describe the discovery of a new class of inhibitors to an essential Streptococcus pneumoniae cell wall biosynthesis enzyme, MurF, by a novel affinity screening method. The strategy involved screening very large mixtures of diverse small organic molecules against the protein target on the basis of equilibrium binding, followed by iterative ultrafiltration steps and ligand identification by mass spectrometry. Hits from any affinity-based screening method often can be relatively nonselective ligands, sometimes referred to as "nuisance" or "promiscuous" compounds. Ligands selective in their binding affinity for the MurF target were readily identified through electronic subtraction of an empirically determined subset of promiscuous compounds in the library without subsequent selectivity panels. The complete strategy for discovery and identification of novel specific ligands can be applied to all soluble protein targets and a wide variety of ligand libraries. Key Words: MurF, Streptococcus pneumoniae, affinity-based HTS, mass spectrometry, promiscuous binder analysis
First published on September 14, 2006, doi:10.1177/1087057106289971 This article has been cited by other articles:
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