Rigidification is often used in designing of a drug to reduce the side effects or increase the activity of the drug. In a flexible molecule with a number of bonds that are rotable in nature, a large number of shapes or conformations can be possible.
The conformation that is recognizable to the receptor is known as the active conformation. The conformations other than this are not able to efficiently interact with the receptor. These are called the inactive conformation.
A drug molecule with higher flexibility has the ability to interact with multiple receptors, and produce significant biological responses. The strategy behind rigidification is to increase the rigidity of the molecule. It employs retention of the molecule’s active conformation as well s reduction of the other conformations that are possible. This strategy is thought to increase the activity of the molecule.
The incorporation of the skeleton of a drug that is flexible is the generally used approach for conformation locking. The given structure can be rigidified by the use of a ring. The bonds around the amino methyl group are rotable in nature that can give rise to both active and inactive conformations. The rotable bonds can be linked within a ring and the active conformation can be fixed.