Paola Ciapetti

Chapter 8 – Molecular Variations Based on Isosteric Replacements

In a biologically active molecule the replacement of an atom or a group of atoms by another one presenting the same physiochemical properties is based on the concept of isosterism. The extensive application of isosterism to modify a part of a biologically active molecule to get another one of similar activity has given rise to the term of bioisosterism or nonclassical isosterism. The development of the concept of isosterism takes its roots in the attempts to extend to the whole molecules the knowledge acquired for elements, namely that two elements possessing an identical peripheral electronic distribution do also possess similar chemical properties. The importance of chemical rings in drug discovery is never overstated. Rings are responsible for the basic shape of the molecule, rendering it rigid or flexible, and are also responsible for a suitable spatial orientation of the pharmacophoric groups. This chapter presents an example to illustrate the possibility to mimick the pyramidal structure of phosphates or phosphonates by means of two planar carboxylic groups, the three-dimensionality originating from the malonic methylenic carbon atom. Most of the studies based on virtual screening use a hierarchical approach combining several conceptually different techniques. Finally, two applications of the bioisosterism concept that imply unusual behaviors of commonly encountered atoms or groups are discussed.