Identification of target family directed bioisosteric replacements

Abstract

Bioisosteres are generally defined as similar chemical groups whose replacement in active compounds retains their biological activity. As such, bioisosteric replacements are of high interest in medicinal chemistry and bioisosterism continues to be an intensely investigated topic. Herein we have investigated the previously unexplored question as to whether bioisosteric replacements can be identified for individual target families. A total of 40 protein families were analyzed. Through a systematic compound data mining effort, we have identified 67 replacements of chemical groups that qualified as bioisosteres for only one target family. These bioisosteric replacements included groups of rather different sizes and chemical compositions and were directed against a total of 12 different target families including, among others, very popular targets such as tyrosine kinases or nuclear hormone receptors. A compendium of target family directed bioisosteric replacements is provided to aid in compound optimization efforts.