Structure Activity Relationship SAR Medicinal Chemistry

Introduction to the topic:

Usually it is obvious from the everyday science of experimentation that similar structures produces the similar biological effect on the body.  Taking a common example of Adrenaline and Nor Adrenaline having almost same structures where N-Methylation of Nor-Adrenaline give Adrenaline. Both have comparable activities usually by striking adrenergic receptors.

Simply it is said that structural Activity Relationships (SAR) are the relations between the molecular structure and biological or physicochemical activity of the drugs. The rational behind SAR is that chemical structure of a molecule determine its physical and biological properties and its reactivity which in interaction with biological system determine its biological and toxicological properties.

Or .The Structure activity relationship (SAR) is a mean by which the effect of a drug or toxic chemical on an animal, plant or the environment can be related to its molecular structure. This type of relationship may be assessed by considering a series of molecules and making gradual changes to them, noting the effect upon their biological activity of each change.

Structure Activity Relationship

Structure activity relationship studies are usually carried out by making minor changes to a previously studied molecules which has some biological activity or the lead (molecule having promising biological activity). By making changes the potency, reactivity , affinity , and toxicological properties of the molecules changes. As far as a drug is concerned, the weapons and armour are the various chemical functional groups present in the structure, which can bind to the receptor or enzyme. We have to be able to recognize these functional groups and determine which ones are important.

The basic assumption of SAR that “molecules having similar structure will have similar activities” is some time exploited in a paradoxical manner. It is not the case everywhere and for all type of assumptions. Sometime structure having similar structures do not show correlation in their activity.

Changes which are done to produce the analogues of a lead for Changing Activity

    1)  The size and shape of the carbon skeleton.

   2)  The nature and degree of substitution.

3  3)  The stereochemistry of the lead.

   1)   Changing the size and Shape of Carbon Skeleton

Changing the size include various changes like:

• ·        Changing the number of methylene  groups in the chains or the rings.
• ·        Increasing or decreasing the unsaturation.
• ·        Introducing or removing the ring or cyclic structure.

1. 1.1                       Changing the number of Methylene Groups

Introduction of Methylene group to the cyclic structure or to the ring increases the lipophilicity of the molecules. Thus leading to the increase in biological activity. But too much elongation of the chain may lead to very high lipophilicity, and bulky structure, thus leading to poor distribution and soluablizaiton in the biological membrane, sequestration (trapping of drugs in the membrane) thus reduction in the activity. Further reduction in the biological activity  is attributed to the chain elongation, promoting micelle formation, because prolong chains easily form micelles.

       1.2)      Increasing or Decreasing the Unsaturation

Saturation of double bond take the carbon atom to have single carbon-carbon bonding. Single bond are more flexible and can easily fit in the receptor. But at the same time removal of double bonding may loss the activity of the double bonding.

Introduction of double bonding lead to rigid structures. And also may lead to E and Z isomerization which may have different activities and some time same activity with different potencies. For Example introduction of double bond at 1-2 position in cortisol form predison which is 30 times more potent then cortisol.

Usually the reactivity of double bonding make the molecule to be more toxic and it is usually undesirable to have double bond introduction. Further more double bond make the structure more prone to metabolic oxidation.

      1.3     Introduction or Removal of Ring system

Introduction or removal of ring system and its effect on activity is un-predictable. Introduction of ring increase the size of the structure and may shape of the overall structure. But for some target sites this increase in the structure fills the hydrophobic pocket this increase the binding to the target.

For example, it has been postulated that the increased inhibitory activity of the cyclopentyl analogue (rolipram) of 3-(3,4-dimethoxyphenyl)-butyrolactam towards cAMP phosphodiesterase is due to the cyclopentyl group filling a hydrophobic pocket in the active site of the enzyme.

    2)    The nature and Degree of Substitution

Similar to the introduction of the Ring introduction substitution is also somewhat un-predictable. It may lead the molecule with different chemical and pharmacokinetic properties. At the same time it may also affect the lipophilicity of the drugs which may affect transport of the drugs. New group introduction may introduce new pathways for metabolism. In nut shell introduction of new substituent may cause lot of changes like increase or decrease of potency, metabolic stability, duration of action and unwanted side effects.  Each substituent will impart different characters to the lead.

  3)   Stereochemistry changes in SAR

Stereochemistry changes are usually done via phenomenon of Isosteres and biosteres. Isosteres are the molecules or atoms having the same number of outer shell electron, which lead them to have the same structure usually. Majority of the lead,s analogues are introduced by preparing their isosteres.