A Novel Class of Inhibitors of Peptide Deformylase Discovered through High-Throughput Screening and Virtual Ligand Screening

Abstract

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.

Integration of virtual screening with high-throughput screening for the identification of novel Rho-kinase I inhibitors

“…HTS based on molecular/cellular assays and large compound libraries have become a central component of modern drug discovery programs (Howard et al, 2004). However, as the available databases get larger, the costs of such screenings rise and the hit rates decrease (Bissantz et al, 2003).…”

Finding ligands for G protein-coupled receptors based on the protein–compound affinity matrix

“…This approach is successful when the target protein structure is properly prepared and the size of the ligand is small [13][14][15][16][17][18][19][20]. The hit ratio of the conventional singletarget in silico screening is low, and several multiple-target screening methods have been proposed to improve it [12,21,22].…”

Isolation and Identification of FR198248, a Hydroxylated 1,3-Dihydroisobenzofuran, fromAspergillus flavipesas an Inhibitor of Peptide Deformylase

“…3,5,6) Some PDF inhibitors have already been reported, although most of them were peptidic. [7][8][9][10][11] In the course of our screening for new PDF inhibitors from microbial resources, highly hydroxylated 1,3-dihydroisobenzofurans, FR198248 (1) and FR202306 (2), were isolated from liquid fermentation cultures of the fungus, Aspergillus flavipes F543. Compound 1 that had previously been isolated from Aspergillus terreus was reported to have anti-influenza activity.…”