Exploring the other side of biologically relevant chemical space: Insights into carboxylic, sulfonic and phosphonic acid bioisosteric relationships

Bioisosteric replacements have been widely and successfully applied to develop bioisosteric series of biologically active compounds in medicinal chemistry. In this work, the concept of bioisosterism is revisited using a novel approach based on charting the "other side" of biologically relevant chemical space. This space is composed by the ensemble of binding sites of protein structures. Explorations into the "other side" of biologically relevant chemical space are exploited to gain insight into the principles that rules molecular recognition and bioisosteric relationships of molecular fragments. We focused, in particular, on the construction of the "other side" of chemical space covered by binding sites of small molecules containing carboxylic, sulfonic, and phosphonic acidic groups. The analysis of differences in the occupation of that space by distinct types of binding sites unveils how evolution has worked in assessing principles that rule the selectivity of molecular recognition, and improves our knowledge on the molecular basis of bioisosteric relationships among carboxylic, sulfonic, and phosphonic acidic groups. (c) 2007 Elsevier Inc. All rights reserved.