Mode of Drug Action

Mode of Drug Action and
Drug Targets
Mode of Drug Action
• Most drugs produce their effects by binding to protein molecules (Drug Target)
• A drug target is a molecule in the body, usually a protein, that is intrinsically

associated with a particular disease process and that could be addressed by a drug
to produce a desired therapeutic effect.
• These are macromolecules that have a binding site into which the drug fits and
binds. Most drugs bind to their targets by means of intermolecular bonds.
• Binding site is an area on surface that has correct shape to accept incoming ligand
• Drug binding often leads to a conformational change in the protein.

Drug Target Sites
Drug interacts with the following target sites on cells:
i. Receptor
ii. Ion channels
iii. Enzymes
iv. Carrier molecules
Important exceptions are cytokines (ligand targeted by mAbs) and DNA

(anti-tumour and antimicrobials)
Drug Binding to Target
Receptors
Receptors are the protein molecules embedded within cell membrane facing
outside, surface being hollow, ravine, ridge or other complicated shapes (binding
site).
They are the sensing elements in the system of chemical communications that
coordinates the function of all the different cells in the body.
When ligand fits into binding site of a receptor, it ‘switches on’ receptor molecule
and a massage is received.
Many therapeutically useful drugs act, either as agonists or antagonists, on

receptors for known endogenous mediators.
Drug-Receptor Interaction
All to do with shape:
Ligand binds to receptor & induces it to change shape
Receptor Related Terminology
Affinity: The capacity of a drug to form the complex with its receptor
(DR complex) e.g., the key entering the hole of the lock has got an
affinity to its levers.
Intrinsic activity (or) Efficacy: The ability of a drug to trigger the

pharmacological response after making the drug-receptor complex.
Ligand: Any molecule which attaches selectively to particular receptors

or sites
Agonists:
─ Agent which activates a receptor to produce an effect similar to that of the
physiologic signal molecule
─ Have both high affinity as well as high intrinsic activity, therefore can trigger the
maximal biological response
Antagonists:
─ Agent which prevents the action of an agonist on a receptor but doesn’t have any
effect of its own.
─ Have only affinity but no intrinsic activity. These drugs bind to the receptor and
block the binding of an endogenous agonist.
Partial agonists:
─ Agent which activates a receptor to produce a sub maximal effect but antagonizes
the actions of full agonist.
─ Have full affinity but with low intrinsic activity and hence are only partly as
effective as agonists.
Inverse (Negative) agonists:

─ Agent which activates a receptor to produce an effect in the opposite direction to
that of the agonist
─ Have full affinity but intrinsic activity ranges between 0 to -1
Ion Channels
✓ Ion channels are protein complexes which traverse cell membrane & consists of
several protein subunits
✓ Core of the complex is hollow and contains polar amino acids to give hydrophilic
tunnel or pore.
✓ Ions cross fatty barrier of cell membrane by moving through hydrophophilic
channels or tunnels.
✓ Some ion channels (known as ligand-gated ion channels or ionotropic receptors)

incorporate a receptor and open only when the receptor is occupied by an
agonist; others are gated by different mechanisms, e.g. voltage-gated ion
channels are particularly important.
✓ The interaction can be indirect, involving a G-protein and other intermediaries,

or direct, where the drug itself binds to the channel protein and alters its
function.
Ion Channels
• Voltage gated-sodium channels are
blocked by local anesthetics
• Benzodiazepine tranquillizers , these

drugs bind to a region of the GABA
receptor-chloride channel complex
Enzymes
Many drugs are targeted on enzymes.
Here the drug molecule is a substrate analogue that acts as a competitive inhibitor
of the enzyme either reversibly (e.g. Neostigmine, acting on acetylcholinestrase) or
the binding is irreversible and non-competitive (e.g. Aspirin, acting on cyclo-
oxygenase).
Drugs may also act as false substrates, where the drug molecule undergoes
chemical transformation to form an abnormal product that subverts the normal
metabolic pathway. Example is the anticancer drug fluorouracil.
Carrier molecules (transporters)
The transport of ions and small organic molecules across cell membranes
generally requires a carrier protein, because the permeating molecules are often
too polar (i.e. insufficiently lipid-soluble) to penetrate lipid membranes on their
own.
There are many examples of such carriers : Glucose and amino acid transporter,
Ion & organic molecule transporters, neurotransmitter precursors (such as
choline) or of neurotransmitters (Noradrenaline, 5-HT, glutamate uptake).
Drug Receptor Interactions
• Majority of drugs show remarkably high correlation of structure and specificity to
produce pharmacological effects.
• A minimum three-point attachment of a drug to a receptor site is required.
• To initiate a biological response, the drug must form bond with the receptor
surface.
• Different types of binding forces that may exist in drug-receptor interactions are
as follows:
─ Electrostatic or Ionic interactions
─ Hydrogen bonding interactions
─ Vander Waals interaction
─ Hydrophobic/Lipophilic interactions
Electrostatic or Ionic Bonds
• An ionic or electrostatic bond is the strongest of the intermolecular bonds (20–40
kJ mol−1 ) and takes place between groups that have opposite charges, such as a
carboxylate ion and an aminium ion
• The strength of the interaction is inversely proportional to the distance between

the two charged atoms and it is also dependent on the nature of the environment
Hydrogen Bonds
• A hydrogen bond can vary substantially in strength and normally takes place
between an electron-rich heteroatom and an electron-deficient hydrogen. The
electron-rich heteroatom has to have a lone pair of electrons and is usually
oxygen or nitrogen.
• The hydrogen bond strength is distance dependent may range from 5 – 7

kcal/mol, depending on the binding environment
Van-der Waals Interactions
✓Van der Waals interactions are very weak interactions that are typically 2–4 kJ
mol−1 in strength.
✓They involve interactions between hydrophobic regions of different molecules,
such as aliphatic substituents or the overall carbon skeleton.
✓The Vander Waals interaction forces occur less frequently than hydrophobic
forces
Hydrophobic/Lipophilic interaction
• Hydrophobic bonds are formed between:
─ Non-polar hydrocarbon groups on the drug and those in the

receptor site.
─ These bonds are not very specific but the interactions do

occur to exclude water molecules

Mode of Drug Action

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Mode of Drug Action and

• A drug target is a molecule in the body, usually a protein, that is intrinsically

• Drug binding often leads to a conformational change in the protein.

Important exceptions are cytokines (ligand targeted by mAbs) and DNA

Many therapeutically useful drugs act, either as agonists or antagonists, on

Intrinsic activity (or) Efficacy: The ability of a drug to trigger the

Ligand: Any molecule which attaches selectively to particular receptors

Inverse (Negative) agonists:

✓ Some ion channels (known as ligand-gated ion channels or ionotropic receptors)

✓ The interaction can be indirect, involving a G-protein and other intermediaries,

• Benzodiazepine tranquillizers , these

• The strength of the interaction is inversely proportional to the distance between

• The hydrogen bond strength is distance dependent may range from 5 – 7

• Hydrophobic bonds are formed between:

─ Non-polar hydrocarbon groups on the drug and those in the

─ These bonds are not very specific but the interactions do

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