Identification of novel fragment compounds targeted against the pY pocket of v-Src SH2 by computational and NMR screening and thermodynamic evaluation.

Discovery of small molecule inhibitors of protein-protein interactions is a major challenge to pharmaceutical development. Fragment-based approaches have begun to be widely adopted as an effective way of exploring chemical space on a protein surface with reduced library size. On completion of a fragment screen, the subsequent selection of appropriate "hit" molecules for development is a key decision point. Thermodynamic parameters can be used in this decision process. In this work, a fragment identification protocol based on a virtual fragment analysis and selection followed by 19F NMR screening was directed at the phosphotyrosine binding site of the Src SH2 domain. Three new ligands were identified. Isothermal titration calorimetry was used to provide thermodynamic parameters for the physiologically relevant ligand and the selected fragments. One of these fragments possesses a highly favorable enthalpic contribution to complex formation compared to other fragments and to the physiologically relevant ligand suggesting that it would make a good candidate for compound development.

Novel 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones as IMPDH inhibitors.

The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors of inosine 5'-monophosphate dehydrogenase type II (IMPDH II).

Quinazolinethiones and quinazolinediones, novel inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure-activity relationships.

The development of a series of novel quinazolinethiones and quinazolinediones as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II and in vitro inhibitory value for PBMC proliferation are discussed.