Structure-Activity Relationship (SAR) is an approach to find the relationships between a chemical structure of a molecule and its biological activity. SARs are usually determined by making minor changes to the structure of a lead to produce analogues and assessing the effect these structural changes have on biological activity.
This activity may be either similar to that of the original compound but different in potency and unwanted side effects or completely different to that exhibited by the original compound.
A study of the structure–activity relationships of a lead compound and its analogues may be used to determine the parts of the structure of the lead compound that are responsible for both its beneficial biological activity, that is, its pharmacophore, and also its unwanted side effects. This information may be used to develop a new drug that has increased activity, a different activity from an existing drug and fewer unwanted side effects.
The investigation of numerous lead compounds and their analogues has made it possible to make some broad generalizations about the biological effects of specific types of structural change. These changes may be conveniently classified as changing:
- the size and shape of the carbon skeleton,
- the nature and degree of substitution, and
- the stereochemistry of the lead.
Changing Size and Shape
The shapes and sizes of molecules can be modified in a variety of ways, such as changing the number of methylene groups in chains and rings, increasing or decreasing the degree of unsaturation and introducing or removing a ring system. These types of structural change usually result in analogues that exhibit either a different potency or a different type of activity to the lead.
Examples of the ways in which the size and shape of the carbon skeletons of lead compounds may be changed to produce new analogues:
Introduction of New Substituents
The new substituents may either occupy a previously unsubstituted position in the lead compound or replace an existing substituent. Each new substituent will impart its own characteristic chemical, pharmacokinetic and pharmacodynamic properties to the analogue. Over the years, a great deal of information has been collected about the changes caused to these properties of a lead compound when a new substituent is incorporated into its structure. As a result, it is possible to generalize about some of the changes caused by the introduction of a particular group into a structure.
However, the choice of substituent will ultimately depend on the properties that the development team decide to enhance in an attempt to meet their objectives.
Moreover, it should be realized that the practical results of such a structural change will often be different from the theoretical predictions.
Examples of some of the groups commonly used as new substituents in the production of analogues:
Analogues formed by replacing an existing group by a new group may exhibit the general stereochemical and metabolic changes. The choice of group will depend on the objectives of the design team. It is often made using the concept of isosteres. Isosteres are groups that exhibit some similarities in their chemical and/or physical properties.
Quantitative Structure ActivityRelationships (QSARS)
Quantitative structure activity relationships are derived for continuous data (e.g., toxic potency data). Which are derived from practical data that is thought to be related to the property the parameter represents.
This makes it possible to either to measure or to calculate these parameters for a group of compounds and relate their values to the biological activity of these compounds by means of mathematical equations using statistical methods such as regression analysis.
QSAR is an attempt to remove the element of luck from drug design by establishing a mathematical relationship in the form of an equation between biological activity and measurable physicochemical parameters. These parameters are used to represent properties such as lipophilicity, shape and electron distribution, which are believed to have a major influence on the drug’s activity.
The development of a QSARs model requires three components:
1) A data set that provides activity (usually measured experimentally) for a group of chemicals (i.e., the dependent variable).
2) A structural criteria or structure-related property data set for the same group of chemicals (i.e., the independent variables).
3) A means of relating (usually a statistical analysis method) these two data arrays. Methods for relating structure to activity range from the simple (i.e., linear regression).