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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