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Drug receptor interaction

This document discusses drug receptor interactions, including definitions of key terms like drug, receptor, antagonist, and pA2 value. It describes how drugs bind to receptors and can act as agonists or antagonists. Quantitative aspects of drug-receptor interactions are covered, including dose-response curves, potency, and therapeutic indices. Factors that contribute to variability in individual responses are also summarized. Binding studies and docking simulations are introduced as methods to study these interactions.

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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 :
Drug receptor interaction