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Peptide deformylase (PDF) has been identified as a promising antibacterial and herbicide target. A structurally novel class of inhibitors containing a 2-thioxo-thiazolidin-4-one heterocycle substituted by an arylidene group at the 5-position and a hexanoic acid side chain at the 3-position was discovered independently via high-throughput screening and virtual ligand screening. Data mining and analogue synthesis established a structure−activity relationship for the side chain region that is consistent with the docked structure.

Virtual library screening (VLS) is emerging as a valuable drug lead discovery tool. ICM-VLS implementation of this technology was evaluated on a benchmark set of nuclear hormone receptors (NRs), an important therapeutic target family. Over 5000 structurally diverse compounds, including 78 known NR ligands, were screened against 18 crystal structures and one computer model of 10 NR ligand binding domains in their active or inactive states. The results confirm the ability of the VLS method to generate highly focused subsets of the input chemical library, enriched 33- to 100-fold for all but one receptor studied. However, receptor flexibility remains to be fully addressed, and the choice of the specific conformation used for screening may determine the success of the exercise. We observe that for a particular ligand VLS can often identify the correct target within the receptor family, although the technology is unable to reliably discriminate between the closely related receptor isoforms. Additionally, our results suggest that VLS may be applied successfully without an experimental structure of the receptor by using a homology model. These data represent a realistic snapshot of the state-of-the-art of NR-targeted VLS and define the recent progress and the remaining limitations of the technology.

Crystallization of the 1:1 molecular complex between the β-lactamase TEM-1 and the β-lactamase inhibitory protein BLIP has provided an opportunity to put a stringent test on current protein-docking algorithms. Prior to the successful determination of the structure of the complex, nine laboratory groups were given the refined atomic coordinates of each of the native molecules. Other than the fact that BLIP is an effective inhibitor of a number of β-lactamase enzymes (KI for TEM-1∼100 pM) no other biochemical or structural data were available to assist the practitioners in their molecular docking. In addition, it was not known whether the molecules underwent conf ormational changes upon association or whether the inhibition was competitive or non-competitive. All six of the groups that accepted the challenge correctly predicted the general mode of association of BLIP and TEM-1.