Drug receptor interaction

DRUG RECEPTOR INTERACTION

MODERATOR: DR. POOJA SHUKLA

RESIDENT: FARIHA FATIMA

JR-II

DRUG:

The WHO (1966) defined it as -

"Drug is any substance or product that is

used or is intended to be used to modify or

explore physiological systems or

pathological states for the benefit of the

recipient."

RECEPTOR:

It describes protein molecules whose

function is to recognise and respond to

endogenous chemical signals.

Other macromolecules with which drugs

interact to produce their effects are

known as drug targets.

ANTAGONIST:

Drugs that block or reduce the action of an

agonist are termed antagonists.

pA2: A pA2 value determines the important relationship

between two drugs "competing" for effect on the same

receptor.

The two drugs are "competitive" if increasing or reducing

one drug decreases or increases the effect of the other,

respectively.

The pA2 value indicates the concentration of antagonist

when double the agonist is required to have the same

effect on the receptor as when no antagonist is present.

Defined as: The negative logarithm to base 10 of

the molar concentration of an antagonist that makes it

necessary to double the concentration of the agonist

needed to elicit the original submaximal response

obtained in the absence of antagonist.

DRUG SPECIFICITY:

The strength of the reversible interaction between a

drug and its receptor.

It is defined as the affinity of one for the other.

A drug that interacts with a single type of receptor that

is expressed on only a limited number of differentiated

cells will exhibit high specificity.

If, however, a receptor is expressed

ubiquitously on a variety of cells throughout the

body, drugs acting on such a widely expressed

receptor will exhibit widespread effects, and

could produce serious side effects or toxicities if

the receptor serves important functions in

multiple tissues.

The pharmacological properties of many drugs

differ depending upon whether the drug is used

acutely or chronically.

In some cases, chronic administration of a drug

causes a down-regulation or desensitization of

receptors that can require dose adjustments to

maintain adequate therapy.

Quantitative Aspects of Drug Interactions with Receptors

The basic currency of receptor pharmacology is

the dose-response (or concentration-response)

curve.

The drug effects can be measured for

quantitative assessment of its safety and

efficacy.

Two ways of quantifying agonism:

Thus, measuring agonist potency by

comparison of EC50 values is one method of

measuring the capability of different agonists to

induce a response in a test system and for

predicting comparable activity in another.

Pharmacodynamic Variability: Individual and Population Pharmacodynamics

Individuals vary in the magnitude of their response to

the same concentration of a single drug or to similar

drugs, and a given individual may not always respond

in the same way to the same drug concentration.

Attempts have been made to define and measure

individual "sensitivity" (or "resistance") to drugs in the

clinical setting, and progress has been made in

understanding some of the determinants of sensitivity

to drugs that act at specific receptors.

Drug responsiveness may change because of

disease or because of previous drug

administration.

Receptors are dynamic, and their concentration

and function may be up- or down-regulated by

endogenous and exogenous factors.

The variability in pharmacodynamic response in

the population may be analyzed by

constructing a quantal concentration-effect

curve.

The dose of a drug required to produce a

specified effect in 50% of the population is the

median effective dose ED50

In preclinical studies of drugs, the median lethal

dose (LD50) is determined in experimental

animals. The LD50/ED50 ratio is an indication of

the therapeutic index, which is a statement of

how selective the drug is in producing its

desired effects versus its adverse effects.

The binding of drugs to receptors : The binding of drugs to receptors can often be

measured directly by the use of drug molecules

(agonists or antagonists) labelled with one or

more radioactive atoms (usually 3H, 14C or 125I).

The usual procedure is to incubate samples of

the tissue (or membrane fragments) with

various concentrations of radioactive drug until

equilibrium is reached.

The bound radioactivity is measured after

removal of the supernatant.

The amount of non-specific binding is estimated

by measuring the radioactivity taken up in the

presence of a saturating concentration of a

(non-radioactive) ligand that inhibits completely

the binding of the radioactive drug to the

receptors, leaving behind the non-specific

component.

This is then subtracted from the total binding to

give an estimate of specific binding .

The binding curve defines the relationship

between concentration and the amount of drug

bound (B), allowing the affinity of the drug for

the receptors to be estimated, as well as the

binding capacity (Bmax), representing the density

of receptors in the tissue.

It has also been shown, in skeletal muscle and

other tissues, that denervation leads to an

increase in the number of receptors in the

target cell, a finding that accounts, at least in

part, for the phenomenon of denervation

supersensitivity.

Non-invasive imaging techniques, such as

positron emission tomography (PET), can also

be used to investigate the distribution of

receptors in structures such as the living human

brain.

Docking studies:

Docking is a method which predicts the preferred orientation

of one ligand when bound in an active site to form a stable

complex.

The ligand is docked onto the receptor and the interactions are

checked. The scoring function generates score, depending on

which the best fit ligand is selected.

Types: Rigid Docking (Lock and Key)

In rigid docking, the internal geometry of both the receptor and

ligand are treated as rigid. In the rigid molecule docking , we relate to

the molecules as rigid objects that cannot change their spatial shape

during the docking process. Flexible Docking (Induced fit)

An enumeration on the rotations of one of the molecules

(usually smaller one) is performed. Every rotation the energy is

calculated; later the most optimum pose is selected.

Importance :