Structure-Activity Relationships Wherever Applicable

The Structure-Activity Relationship (SAR) is the concept of analysing the biological activity of any compound from its molecular or chemical structure. This technology is used to study the various aspects of drugs, like screening for optimisation of their properties and new drug discoveries.

Crum-Brown and Fraser proposed SAR in 1865. This detailed inspection of the chemical structure helps to estimate the biological effect on the target evoked by the functional group attached to the chemical structure. Medicinal chemists utilise this technique to enhance drug potency through modifications and testing. 

Medicinal Chemistry

Medicinal chemistry, practised by medicinal chemists, implements organic chemistry to prepare pharmaceutical drugs or agents.

The pharmaceutical drugs or agents are categorised into classes made up of small molecules. A class has a similar base structure and properties.

For example, Penicillin G, Amoxicillin, and Ampicillin all belong to the same penicillin class and have similar base structures.

The structure of the drug defines the function. The chemical synthesis of drugs or pharmaceutical agents is done based on the base structure and the functional groups added as ligands.

Discovery of New Drugs

The discovery of new chemical compounds is called “hits”. This is done either by reanalysing the already existing drugs or by studying the behaviour of biological compounds found in various life forms. The chemical synthesis of fragments forms more significant compounds depending on how different compounds bind with proteins and receptors.

The hits need to undergo several steps before attending the final status of the drug. Some hits are stored in chemical libraries for future testing and discoveries.

Hits undergo confirmatory testing to check if they are reproducible. This is followed by concentration testing to test the binding capability and bioavailability of the hits. After that, hits undergo a series of tests such as synthetic tractability to test their actual ability to be produced on a large scale. Other tests include biophysical testing, kinetic, thermodynamics, and stoichiometry testing for conformational changes, ranking and clustering, and finally, freedom to operate evaluation to check if the product is patentable.

After the tests, the hits become lead. This optimises the hit compound to improve its efficiency, and reduce its side effects and off-target activity. The phase that follows the lead is drug candidate. Many compounds run through this cycle several times and then go to the next phase called pre-clinical, followed by the final phase called clinical and are fit for use.

Quantitative Structure-Activity Relationship

Quantitative Structure-Activity Relationship (QSAR) is a structure-activity model for biological and chemical engineering classification. QSAR models map a set of predictor variables to a set of response variables of a category.

The predictor variables in the QSAR model are the physicochemical properties of a pharmaceutical drug or compound, whereas the response variables are the biological activities of the targeted receptor.

This model works in phases. It first summarises the relationship between the biological activity and chemical structure of the predictor and receptor being tested. Then in the second phase, it foretells the behaviour of the new compounds.

Biological activity can be expressed quantitatively as the concentration of chemical substances reflecting a certain response. The physicochemical properties are an addition to the calculation process as the values of these properties are in numbers. Hence, QSAR can be expressed in the mathematical model as:

f (physicochemical properties and/or structural properties) + error = Activity 

The error can be a model error or due to variability in observation.

Applications of Structure-Activity Relationship

Chemical and Physical Property Formulation of Compounds

This application is prominent in medicinal chemistry, where medicinal chemists use SAR analysis to prepare new drugs depending on the base structure of similar compounds.

Estimation of Toxicity in the Compounds

SAR studies the toxicity of the compounds. Toxicity refers to anything unwanted and harmful to the receptor. Overdosage of any drug results in toxicity, whereas its underdosage becomes ineffective for the receptor. The correct concentration and its effectivity are calculated using the SAR.

Drug Receptor Reciprocation

The drugs bind to the receptor, either with a reversible ionic bond or an irreversible covalent bond. SAR can be studied using silico methods to know the target and drug interactions. 

Pharmacokinetics of Drugs

SAR is used to calculate the solubility, metabolism, rate of reaction, and other factors between drugs. Excretion and distribution of drugs are factors of the pharmacokinetics of a compound. This helps in estimating the physicochemical property of the drug and, hence, the efficiency.

Drug modification for Enhancements

The SAR provides the biological effects of any compound, mostly drugs. Once the biological effect is studied, it becomes easier for medicinal chemists to modify the potential of that drug as a bioactive compound. The modification is done by changing the chemical structure of the compound.

Conclusion

The Structure-activity relationship or SAR is a boon to the field of medicinal chemistry. The study and development of medicine concerning the biological activity, binding of proteins and ligands in the target, their solubility, reproducibility, etc. The results of SAR are usually presented in the form of tables and graphs. It is readable and can be termed a medical and chemical science milestone.