Donald B. Boyd, Department of Chemistry, Indiana University-Purdue University at Indianapolis, 402 North Blackford Street, Indianapolis, Indiana 46202-3274, U.S.A.
Computational chemists have been engaged in computer-aided molecular design for more than three decades. Computer-aided drug design (CADD) is common term for the technology applied to the discovery of bioactive compounds. However, the term describes the objective, but not generally what the computer actually does. It is impossible to expect a molecular structure to appear on the screen of the workstation simply by asking the computer for a novel molecule that will cure cancer, is inexpensive to manufacture, and has no side effects. Rarely does computational chemistry lead directly to a medicine. The much more common scenario is that the computer is used to stimulate ideas and test hypotheses for novel ligands, i.e., small molecules that bind specifically to some larger biomolecule. If these ligands are synthesized and pass all the many tests for biological activity, specificity, bioavailability, lack of toxicity, medical need, market potential, and so on, then one of these ligands may become a pharmaceutical. The term computer-aided ligand design (CALD), which we first suggested in 1993, better describes what the typical computational chemist in pharmaceutical research actually does. The goal is to use the methodologies of computational chemistry to help to discover chemical structures with properties that might qualify them to enter the pharmaceutical discovery pipeline. At the time when combinatorial chemistry has gained the spotlight from molecular modeling and structure-based approaches, it is useful to review where computational techniques have been particularly useful. Examples of demonstrable achievement are presented.