Background: In the rational drug development field, bioisosterism is a tool that improves
lead compounds' performance, referring to molecular fragment substitution that has similar
physical-chemical properties. Thus, it is possible to modulate drug properties such as absorption,
toxicity, and half-life increase. This modulation is of pivotal importance in the discovery, development,
identification, and interpretation of the mode of action of biologically active compounds.
Objective: Our purpose here is to review the development and application of bioisosterism in drug
discovery. In this study history, applications, and use of bioisosteric molecules to create new drugs
with high binding affinity in the protein-ligand complexes are described.
Methods: It is an approach for molecular modification of a prototype based on the replacement of
molecular fragments with similar physicochemical properties, being related to the pharmacokinetic
and pharmacodynamic phase, aiming at the optimization of the molecules.
Results: Discovery, development, identification, and interpretation of the mode of action of biologically
active compounds are the most important factors for drug design. The strategy adopted for
the improvement of leading compounds is bioisosterism.
Conclusion: Bioisosterism methodology is a great advance for obtaining new analogs to existing
drugs, enabling the development of new drugs with reduced toxicity, in a comparative analysis with
existing drugs. Bioisosterism has a wide spectrum to assist in several research areas.