In drug designing, a frequently encountered problem is trying to decide what the active conformation of a molecule is, when it fits into its target binding site. It is particularly true for simple and flexible molecules. This is because these types of molecules can adopt better to a large number of conformations.
It is not necessary that the most stable conformation is also the most active one. In some cases, the drug can form a stable complex with its target but it may not be active. This would mean, despite stability, the drug cannot perform its function successfully. Sometimes, a less stable conformation of a molecule can possess the active conformation.
This is because the drug binding with the target site leads to stabilization of the energy, while the energy required to adopt its active conformation is compensated by this. The active conformation of a molecule can be identified by X-ray crystallography and by comparing rigid structures with non-rigid ones.
The study of X-ray crystal structure of a target protein with its attached ligand or drug is the easiest way of identifying an active conformation of the molecule. The presence of a rigid molecule, which has only one possible conformation, in one of the active compounds helps in identifying the active conformations.