Question

How does structural modification lead to understanding of how structure influences activity and pharmacokinetics for extension, isosteres, simplification, and chirality?

Answer 1

To develop the desired therapeutic effect, the drug should reach the site of action in sufficient concentration and also should reach in a timely manner. For example, an orally administered drug has to withstand the acidic environment in the stomach for it's absorption to the bloodstream from the small intestine where the majority of absorption takes places.

Pharmacokinetics means the collective process of the distribution of the drug in the body, the degree of metabolic transformation, the rate of absorption and it's excretion. Hence, Pharmacokinetics is the influence of the body on a drug as a function of time. Pharmacodynamics is the consequences of the interaction of the drug with its target as a function of time.

The chemical structure of a drug determines its Pharmacokinetics and Pharmacodynamics. Any defects in the Pharmacokinetics and Pharmacodynamics of a drug can be corrected by structural modifications. The structural modification will help in optimizing the desired therapeutic effects and minimizing the unwanted side effects.

The bioisosteres are used to optimize the biological activity of a drug. In bioisosteres, the functional groups or atoms of the parental molecules are modified for obtaining the optimized biological activity. This molecular mimicry or bioisosteres replacement will change the physicochemical properties of the resulting molecule and thus will help in the production of a more therapeutically effective drug. This structural changes will affect the Pharmacokinetics and Pharmacodynamics of the drug. That means, the structural changes will affect the solubility, chemical reactivity, metabolism of the drug, it's bioavailability, it's potency etc. The bioisosteres replacement in a particular pharmacological group may not be effective in another pharmacological group which is acting on another target.

Pharmacological targets like enzymes and receptors are usually protein compounds and thus highly chiral in nature. Other targets like macromolecules and DNA are also built by chiral building blocks. Hence, many of the pharmacological products are chiral drugs. Enantiomers of chiral drugs have the same chemical connectivity, but they show different  Pharmacokinetics and Pharmacodynamics. The tragic cases of fetal abnormalities due to the teratogenic effect of thalidomide was because of the S-enantiomer whereas the R-enantiomer was having the desired effect.