Small molecule drugs comprise multi-dimensional features, and drug creation has to meet requirements such as safety, effectiveness, stability, controllability, and patient compliance. These attributes can be summarized as pharmacological activity and druglikeness, which are implicit in the chemical structure of the drug. Pharmacological activity and adverse reactions are caused by the interaction between drug molecules and on-target or off-target protein. The microstructure of the drug determines the activity/toxicity intensity and selectivity. Pharmacokinetic and physicochemical properties are related to the macroscopic properties of the drug, and the microstructure and macroscopic properties are intertwined and integrated into the molecular structure. Conception and construction of bifunctional molecules are one of routes to achieve "unification of micro and macro" and structurally straighten out the relationship between pharmacodynamics-pharmacokinetics, drug efficacy-adverse reactions (selectivity). This article takes drugs that have been successfully marketed or under clinical trials as examples to explain the structural characteristics of bifunctional molecules from the viewpoint of medicinal chemistry. The productive technical methods include antibody-drug conjugate, proteolysis-targeting chimeras, molecular glues, peptide modifications, and so on. In addition, this overview also classifies covalently binding drugs, transition-state analogs, and prodrugs into the category of bifunctional molecules, emphasizing the importance of bifunctional groups in molecular design and structure optimization.

bifunctional molecule  /  antibody-drug conjugate  /  proteolysis-targeting chimeras  /  molecular glue  /  covalent binding drug  /  transition state analog  /  prodrug