Assessing Bioisosteres Nonbonded Interactions

Much of our current knowledge of intermolecular interactions has been derived from the study of crystal structures. For example, it was not until an extensive survey of 1509 N—H---0=C hydrogen bonds in CSD structures that the O lone pair directionality of this key interaction was first recognized [31]. Another example is the detailed study of hydrogen bond geometries in 15 globular proteins carried out by Baker and Hubbard [32] and these hydrogen bond definitions, derived nearly 30 years 

One particularly effective example of the use of IsoStar was in the design of inhibitors for the N-methyl D-aspartate (NMDA) receptor. Here two known inhibitors, kynurenic acid and arylideno-imidazolinonoyl-glycine, were decomposed into functional groups and their interaction patterns analyzed in IsoStar. Armed with this information, the binding mode was rationalized and a simple pharmacophore of the NMDA receptor was created [36]. The pharmacophore was able to explain activity data of compounds derived from the original inhibitors modified by esterification [37], and was also able to inspire a new set of inhibitors with improved pharmacochemical properties [38]. 

---