SB-207499 phosphodiesterase(pde) is not well placed for binding with thiazolidinedione ring.

l 5 is not well placed for binding with SB-207499 phosphodiesterase(pde) the thiazolidinedione ring. The synthesis and assay of thiazolidinedione derivatives is widely used. They have been described positively as privileged scaffolds or negatively as frequent hitters or PAINS. As well as inhibiting PI3K, thiazolidinedione derivatives are clinically used PPARγ agonists and aldose reductase inhibitors , and have research applications as antibacterial, antimalarial, anti-inflammatory, antiviral, herbicidal, insecticidal, antifungal, anticancer, anthelmintics, and for treatment of Alzheimers disease, CNS disorders, diabetes, cardiovascular, cystic fibrosis and thrombocytopenia.
They bind to targets as diverse as G-Protein-coupled receptor 40 , protein tyrosine Canertinib phosphatase 3 , cyclooxygenase 2 , MurB, C & G, B-cell lymphoma-2 , phosphodiesterase 4 , fungal protein mannosyl transferase 1 , tumour necrosis factor alpha , Hepatitis C virus nonstructural protein 3 and NS5b polymerase , cytosolic phospholipase A2α , proto-oncogene serine/threonineprotein kinase , cyclin-dependent kinase 2 , HIV-1 integrase, serotonin N-acetyltransferase and glycogen synthase kinase-3β. Several of the most potent compounds identified here have also been picked up in other screening campaigns, offering a cautionary note to the possibility of off-target effects. Frequent reporting in their identification via screening may be due to the low IC50 activity assigned for a hit which is often ~ 25 μM, representing only weak affinity for the target of interest.
On the other hand, the drug-like properties of low molecular weight, low logP, presence of both hydrogen bond donors and acceptors, and the capacity for multiple approaches to structural elaboration recommend them as small molecules in a fragmentbased screening approach, and the perceived limitations could be addressed by structural modification. Conclusion In summary, having noted the report of PI3Kγ thiazolidinedione inhibitors in the literature, we devised a broadened library aiming to discover inhibitors targeting the PI3Kα isoform and twelve inhibitors of submicromolar IC50 were identified. We attempted in silico docking experiments and showed that the active compounds could be readily identified from decoy compounds. Docking results were improved by using higher resolution structures and liganded structures of the PI3Kγ- and PI3Kδ-isoforms which perform better than the apoform of the actual target, PI3Kα.
It was interesting that in this case, homology of the protein to the target was less important than presence of a ligand in the binding site or resolution of the structure chosen. Improved enrichment using a PI3Kα structure was observed with the use of induced fit virtual screening experiments for a PI3Kα homology model, rather than the apo-structure. The homology models derived from induced fit docking studies showed that specific conformers surrounding key residues markedly influence the docking result. As a validation of the use of virtual screening in this context, it is apparent that with the correct selection of protein model, most of the potent inhibitors could be identified from the decoy set.
With a reliable model of PI3Kα in hand, docking could be well utilized in future screening campaigns for isoform selective compounds. Pinson et al. Page 7 ChemMedChem. Author manuscript; available in PMC 2011 October 5. HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscript Experimental Section Chemistry All chemical reagents acquired from Sigma-Aldrich and Fluka were used without further purification while compounds 40�?2, 44�?7 and 49�?3 were acquired from Maybridge. Experimental data on synthesiz