Desain Obat

Lia Puspitasari, M.Si.,Apt.

P.2 DRUG ACTIONS
Drugs are designed to exert
• a selective influence on vital processes
• to alleviate or eliminate symptoms of disease

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 How drug works in the body
• Drugs with Non-specific target
• Drug with Specific target

three main drug targets

(1) lipids
(2) Receptor proteins (glycoproteins)
(3) nucleic acids

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 Receptors
* macromolecules that operate to bind
messenger substances and transduce this
binding into an effect, i. e., a change in cell
function.

• specific areas of certain proteins and

glycoproteins that are found either
spanning cellular membranes or
in the nuclei of living cells.

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outer cell membrane

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 structure of the cell

-Highly prganized
-Functional organelles
* mitochondria
* endoplasmic reticulum
* Golgi apparatus
* lysosome
* centrioles

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 Cell functions
coordinated by means of
• cytosolic contacts between neighboring cells
(gap junctions,
e. g., in the myocardium)
• messenger substances
for the transfer of information

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 Receptor ligand
any endogenous or exogenous chemical agent that binds to a specific
receptor

Endogenous signaling chemicals

– Hormones secreted by endocrine glands into the blood, then
into the extracellular fluid
– neurotransmitters
– the prostaglandins and cytokines

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 Signal transduction
Translation of the message carried by the ligand
through the receptor into a physiological
response
Receptor + ligand  complex R-L

Physiological response

Receptor ligands may be endogenous or exogenous substance

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Cellular Sites of drug actions
 modifying cell function

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Neurotransmitter action on its specific
receptor

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Binding of a messenger to a receptor

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 ligand–receptor interactions
• causes the opening or closing of ion channels
• release of secondary messengers

which promote a sequence of biochemical

events that result in an appropriate
physiological response

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 Drug actions
The binding of a drug to a receptor either inhibits or stimulates its action, which
ultimately results in the physiological responses that are characteristic of the
action of the drug.

Alter activity of membrane transport systems

e. g. cardiac glycosides
loop diuretics
calcium antagonists,

Directly interfere with intracellular metabolic processes

• by inhibiting an enzyme (phosphodiesterase inhibitors)
• by activating an enzyme (organic nitrates)
• By affecting processes in the cell nucleus affected
(e. g., DNA damage by certain cytostatics).

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Ion channel protein structure

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Opening of ion channel

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ACETHYLCHOLINE

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.

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 Phospholipid membrane
The cell membrane basically consists of a
phospholipid bilayer (50 Å = 5 nm in thickness),

The hydrophobic interior of the phospholipid membrane constitutes a

diffusion barrier virtually impermeable to charged particles.

Apolar particles are better able to penetrate the membrane  of major

importance with respect to the absorption, distribution, and
elimination of drugs.

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 G-Protein coupled receptors
Binding of the mediator molecule or of a structurally
related agonist molecule induces a change in the
conformation of the receptor protein, enabling the latter
to interact with a G-protein (= guanyl nucleotide-binding
protein)

• consist of an amino acid chain that weaves in and out of

the membrane in serpentine fashion.

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G-proteins coupled receptors

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 G-proteins
G-proteins (= guanyl nucleotide-binding protein)lie at the inner leaf of the
plasmalemma andconsist of three subunits designated α, β,and γ.

There are various G-proteins that differ mainly with regard to their α-unit.

Association with the receptor activates the G-protein, leading in turn to

activation of another protein (enzyme, ion channel).

A large number of mediator substances act via G-protein-coupled

receptors

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 ligand-gated ion channel
the nicotinic cholinoceptor of the motor end plate

Simultaneous binding of two acetylcholine

(ACh) molecules to the two α-subunits results
in opening of the ion channel with entry of
Na+ (and exit of some K+)

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 Protein synthesis regulating receptors

for steroids and thyroid hormone are found intracellularly

• in the cytosol (e. g., glucocorticoids, mineralocorticoids,
androgens, and gestagens)
• in the cell nucleus (e. g., estrogens, thyroid hormone).

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 Bonding interactions
between substrate and enzyme

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 Example of induced fit: pyruvic acid

In order to maximize the strength of these bonds, the enzyme would

have to change shape so that the amino acid residues involved in the binding move
closer to the substrate

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 Intermolecular interactions

a drug usually attaches to its site of action by

multiple contacts of several types of bonds

Types of Bond
• Covalent Bond
• Noncovalent bond

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 Covalent Bond

Two atoms enter a covalent bond if each

donates an electron to a shared electron pair.

The covalent bond is “firm,” that is, not

reversible or poorly so.

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 Drugs covalently bound to biological
structures

 Biological structures of microbes/parasites 

inhibition/cessation of growth

 Biological structures of human patients The bond, and

possibly the effect, persist for a long time after intake of a drug
has been discontinued
 making therapy difficult to control

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Alkylating cytostatic anticancer

Covalently bound at double helix

DNA

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 The danger of covalent bonded drug to
biogenic molecules
Certain organic phosphoric acid compounds
bind with high affinity to a serine OH group in
the active center of AChE and thus block the
hydrolysis of acetylcholine.

As a result, the organism is poisoned with its

own transmitter substance, acetylcholine.

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Covalent bonded organophosphates

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 covalently bound foreign substances

organophosphates enjoy widespread application as

insecticides. Their use has led to human poisoning
because these toxicants can enter the body through the
intact skin or inhaled air.

Depending on the severity, signs of poisoning include

excessive parasympathetic tonus, ganglionic blockade,
and inhibition of neuromuscular transmission leading to
peripheral respiratory paralysis.

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 Covalently bonding drugs as potentially
Biological weapons
the organophosphates have been misused as
biological weapons.

In the present global situation, the fear has

arisen that organophosphates may be used by
terrorist groups.
Thus, understanding the signs of poisoning and
the principles of treatment are highly
important.

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 Noncovalent Bond

The bond is reversible and is typical of most

drug–receptor interactions in human body.

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Noncovalent interactions

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 Electrostatic attraction
A positive and a negative charge attract each other.

Ionic interaction: An ion is a particle charged either positively (cation) or

negatively (anion), i. e., the atom is deficient in electrons or has surplus
electrons, respectively.

Attraction between ions of opposite charge is inversely proportional to the

square of the distance between them; it is the initial force drawing a
charged drug to its binding site.

Ionic bonds have a relatively high stability.

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 Dipole–ion interaction
When bonding electrons are asymmetrically distributed over the atomic
nuclei involved, one atom will bear a negative (δ–), and its partner a
positive (δ+) partial charge.

The molecule thus presents a positive and a negative pole, i. e., it has
polarity or is a dipole. A partial charge can interact electrostatically
with anion of opposite charge.

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 Dipole-dipole interaction

the electrostatic attraction between opposite

partial charges.

When a hydrogen atom bearing a partial positive

charge bridges two atoms bearing partial
negative charges, a hydrogen bond is created.

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 van der Waals bonds
formed between apolar molecular groups that have come
into close proximity.
Spontaneous transient distortion of electron clouds
(momentary faint dipole, δδ) may induce an opposite
dipole in the neighboring molecule.

The van der Waals bond, therefore, is also aform of

electrostatic attraction, albeit of very low strength
(inversely proportional to 7thpower of distance).

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Vander Waals bonding

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 Hydrophobic interaction
The attraction between the water dipoles is strong enough
to hinder intercalation of any apolar (uncharged)
molecules.

By tending toward each other, H2O molecules squeeze

apolar particles from their midst. Accordingly, in the
organism, apolar particles such as fatty acid chains of cell
membranes or apolar regions of a receptor have an
increased probability of remaining in nonaqueous, apolar
surroundings.

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Hydrophobic interaction

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 Agonists—Antagonists

An agonist (A) has affinity (tendency to adhere) for a receptor and affects
the receptor protein in such a manner as to cause achange in cell
function—“intrinsic activity.”

Antagonists (A) attenuate the effect of agonists: they act

“antagonistically.”

Competitive antagonists possess affinity for the receptors, but their

binding does not elicit a change in cell function (to be devoid of
intrinsic activity)

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 Molecular mechanism of agonist

Agonist induces an active conformation. The agonist binds to the inactive

receptor and thereby causes the resting conformation to change into the
active state.

Allosteric antagonist is bound outside the agonist’s site of attachment at the

receptor and induces a decrease in agonist affinity.

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Agonist and antagonist

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