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DRUG TARGET

RESEPTOR
Merupakan molekul protein yang terikat
pada membran dan sebagian dari
strukturnya terpapar ke bagian luar sel.
Memiliki sisi pengikatan ( binding site).
Reseptor berbeda
dengan enzim.

secara

mendasar

SIGNALING
Messenger + reseptor

Perubahan bentuk Reseptor

Komponen membran sel terpengaruhi


Efek biologis
Dua komponen utama yang terlibat yaitu :
saluran ion (ion Channels)
enzim yang terikat pada membran (membrane-bound enzymes)

SALURAN ION
Neurotransmitter yang dilepaskan oleh syaraf
dapat menyebabkan efek biologis pada sel
target.
menginduksi perubahan konformasi reseptor -->
terbukanya beberapa ion channel.

dua mekanisme keluar masuknya molekul


polar melintasi membran, yaitu :
1.Melalui transpor protein
2.Melalui saluran ion

Transpor Protein
Struktur protein ion channels.

LOCK GATE MECHANISM


pembawa pesan terikat, perubahan bentuk reseptor
menyebabkan lock gate terbuka dan ion dapat masuk, dan
sebaliknya.

MEMBRAN BOUND ENZYMES


Ketika protein reseptor terikat pada
neurotransmiternya bentuk reseptor
berubah dan menyebabkan perubahan
bentuk dari enzim

MEMBRAN BOUND ENZYMES

MEMBRAN BOUND ENZYMES


The centre of the cylinder can act as
an ion channel for sodium
A gating or lock system is controlled
by the interaction of the receptor with
acetylcholine
The binding site for acetylcholine is
situated on the alpha subunit and
there
fore there are two binding sites per
receptor protein
Nicotinic Recetor

DESAIN AGONIS
bagaimana merancang suatu obat yang
memiliki sifat menyerupai/ meniru
senyawa alami.
Kriteria (secara umum)
1. Obat harus memiliki kelompok ikatan yang tepat
2. Kelompok ikatan pada obat harus berada pada
posisi yang benar
3. Obat harus memiliki ukuran yang sesuai dengan
situs pengikatan (binding site)

DESAIN AGONIS
BINDING GROUP
Senyawa dengan struktur yang berbeda,
namun memiliki kelompok ikatan yang
diperlukan untuk berinteraksi dengan
reseptor potensial menjadi agonis.

DESAIN AGONIS
BINDING GROUP

DESAIN AGONIS
POSISI IKATAN
The molecule may have the correct binding groups, but if they are in the wrong
relative positions they will not be able to form bonds at the same time. As a result,
bonding would be too weak to be efective

DESAIN AGONIS
POSISI IKATAN

The structure has the same formula and


the same constitutional structure as our
original structure.

Therefore, the activity of apparently


disparate structures at a receptor can
be explained if they all contain the
correct binding groups at the correct
positions

DESAIN AGONIS
SIZE AND SHAPE
It is possible for a compound to have the correct binding groups in the correct
positions and yet fail to interact efectively if it has the wrong size or shape (steric
factor)

DESAIN ANTAGONIS
Senyawa antagonis : menghambat agonis untuk
berikatan sehingga tidak mengaktifkan reseptor
dua jenis antagonis, yaitu :
1. Antagonis yang bekerja pada binding site
2. Antagonis yang bekerja diluar binding site

DESAIN ANTAGONIS - BS

design a drug that is the right shape to bind to the


receptor binding site, but which either fails to change
the shape of the binding site or distorts it in the
wrong way

DESAIN ANTAGONIS - BS

DESAIN ANTAGONIS - BS

Therefore, the molecule acts as an antagonist; it binds to the


receptor, but fails to activate it

DESAIN ANTAGONIS - BS
17-Estradiol is a steroid hormone that
affects the growth and development of a
number of tissues

Estradiol uses its alcohol and phenol


groups to form hydrogen bonds with three
amino acids in the binding site, while the
hydrophobic skeleton of the molecule
forms van der Waals and hydrophobic
interactions with other regions

DESAIN ANTAGONIS - BS
17-Estradiol is a steroid hormone that
affects the growth and development of a
number of tissues

Estradiol uses its alcohol and phenol


groups to form hydrogen bonds with
three amino acids in the binding site,
while the hydrophobic skeleton of the
molecule forms van der Waals and
hydrophobic interactions with other
regions

Estradiol

DESAIN ANTAGONIS - BS
Raloxifene has two phenol groups that
mimic the phenol and alcohol group of
estradiol. The skeleton is also hydrophobic
and matches the hydrophobic character
of estradiol

Raloxifene

DESAIN ANTAGONIS - dBS


How do these antagonists work?

1. Antagonis alosterik
2. Antagonis dengan efek umbrella

DESAIN ANTAGONIS - dBS


1.

Antagonis alosterik

DESAIN ANTAGONIS - dBS


2. Antagonis dengan efek umbrella

afinity of a drug for a receptor : measure


of how strongly that drug binds to the
receptor.
Effiacy : measure of the maximum
biological effect that a drug can produce as
a result of receptor binding.
The potency of a drug : the amount of
drug required to achieve a defined
biological effect
How to measure it?
radioligand labelling

RADIOLIGAND LABELLING

Potensi dari Agonis dinyatakan dengan


EC50 yaitu kosentrasi yang menyebabkan
munculnya 50% efek

DESAIN ANTAGONIS/AGONIS

To sum up, if we know the shape and characteristics


of a receptor binding site then we should be able to
design drugs to act as agonists or antagonists
determining the layout of a receptor binding site is
not as straightforward as it sounds

GOUT DRUGS :
MOLECULAR APPROACH DESIGN
TO INHIBITS THE ACTIVITY OF XANTHINE OXIDASE

MECHANISM OF DISEASES
metabolic disease that results
from hyperuricemia, an
elevation in the blood of uric
acid, the end-product of purine
degradation

Imbalance between elimination


and production of uric acid
uric acid is the end product of the degradation of purines. Uric
acid serves no known physiologic purpose and therefore is
regarded as a waste product

PHYSICOCHEMICAL OF URIC ACID

weak acid (pKa = 5.6 5.75) at


physiologic pH, most of plasma
uric acid is in the ionized
saturating concentration of
monosodium urate 37C is
about 420mol/L (7 mg/dL)

uric acid is only 1/20 as


soluble as sodium urate

Solubility is markedly reduced as the


temperature fails, protein binding and
other molecule
Urate is less soluble at lower temperature,
which may explain the peripheral
distribution of urate crystal deposition

PHYSICOCHEMICAL OF URIC ACID

(Abbas, Robbins, Kumar, Collins, & Cotran, 2005)

DRUG TARGET AND MECHANISM


Modify purine metabolism to achieve normal
concentrations of plasma urate

Control Pain

DRUG TARGET AND MECHANISM


Inhibits one or more enzymes in purine metabolism
Allopurinol, Febuxostat (Xanthine Oxidase Inhibitor)

enhance the excretion of plasma urate


Probenecid, Sulfinpyrazone, Losartan, Benzbromarone
(Tubular Reasorbtion Blocker, Uricosoid)

Exogenous of Uricase (Enhance Uric acid Metabolism)

NEW DRUG DESIGN : XO

molybdopterin-containing flavoproteins
that consist of two identical subunits

one molybdopterin cofactor,


two spectroscopically distinct [2Fe-2S]
centers, one FAD cofactor

NEW DRUG DESIGN : XO

Xanthine and hypoxanthine are oxidized at the molybdenum


center
The metal being reduced from the VI to the IV valence state
The reducing equivalents are transferred to molecular oxygen at
the FAD with the mediation of the iron-sulfur centers

NEW DRUG DESIGN : XO

NEW DRUG DESIGN : XO

Allopurinol was initially synthesized as an attempt to produce


new antineoplastic agents in the mid-1950s by Falco
The early search for novel XO inhibitors focused on
synthetic purine and pyrimidine derivatives

But the side effect is still the same as allopurinol


A search for new XO inhibitors that are
structurally distinct from purines

RATIONAL DRUG DESIGN: XO

Based on rational design of the interaction ligand : xanthine


and hypoxanthine

RATIONAL DRUG DESIGN: XO


oxidations occur at the MoOS unit of XO, hypoxanthine must
approach MoOS with its C2 oxidable carbon atom, xanthine with its
C8 carbon atom

C2 of hypoxanthine must be assumed to be geometrically


equivalent with C8 of xanthine
(center 1)
implies that the six-membered ring of one substrate is geometrically
equivalent with the five-membered ring of the other

RATIONAL DRUG DESIGN: XO

The distance of 1h - 1x is 0.38, 2h 3x = 0.57, 2x 3h


= 0.78, 4h 4x = 0.69. Where h = hypoxanthine and x =
xantine (Rastelli, Costantino, & Albasini, 1997)

the equivalence of the geometrical centers of the two rings


(centers 2 and 3)
the carbonyl oxygen
O6, there is a complete loss of catalytic activity in purine
analogs in which the carbonyl group is replaced by a
methyl (6-methylpurine) and a methoxyl (6-

(center 4)

RATIONAL DRUG DESIGN: XO

1. Reactive center, the site that can be oxidized by XO. The new
drug design is need to have the reactive center that can be
oxidized by XO, just like xanthine and hypoxhantine.

Carbonyl, which is react on the amino acid of the XO that can


form a bound from drug to XO.

1. Geometric center of the rings. The similarity to the substrate of


XO.

RATIONAL DRUG DESIGN: XO

RATIONAL DRUG DESIGN: XO

flavonoid

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