Among all new technologies in drug research, structure-based ligand design is one of the most powerful approaches. The drugs Captopril, Dorzolamide and Zanamivir, to mention only some prominent examples, resulted from rational design, based on the knowledge and analysis of protein 3D structures. The discovery of some other drugs, e.g. the more recent HIV protease inhibitors Nelfmavir and Amprenavir, was at least supported by protein crystallography studies. Many other drug candidates that resulted from structure-based design are in clinical development.
Whereas some early attempts of structure-based design failed due to inappropriate physicochemical and pharmacokinetic properties of the ligands, modellers are nowadays aware of the pitfalls in ligand design. Large, greasy ligands are avoided, as well as too polar compounds. According to favorable lead and drug properties, defined e.g. by the Lipinski rule of five, ligand design focuses on compounds with relatively low molecular weight, an intermediate lipophilicity range, and a limited number of hydrogen bond donors and acceptors.