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7/23/2019 Target Kerja Obat (Reseptor)
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DRUG TARGET
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RESEPTOR
• Merupakan molekul protein yang terikatpada membran dan sebagian daristrukturnya terpapar ke bagian luar sel.
• Memiliki sisi pengikatan ( binding site).
• Reseptor berbeda secara mendasar dengan enzim.
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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)
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SALURAN ION
• Neurotransmitter yang dilepaskan oleh syarafdapat menyebabkan efek biologis pada seltarget.
• menginduksi perubahan konformasi reseptor -->terbukanya beberapa ion channel.
• dua mekanisme keluar masuknya molekulpolar melintasi membran, yaitu :
1.Melalui transpor protein
2.Melalui saluran ion
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Transpor ProteinStruktur protein ion channels.
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LOCK GATE MECHANISM
pembawa pesan terikat, perubahan bentuk reseptor
menyebabkan lock gate terbuka dan ion dapat masuk, dan
sebaliknya.
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MEMBRAN BOUND ENZYMES
• Ketika protein reseptor terikat pada
neurotransmiternya bentuk reseptor
berubah dan menyebabkan perubahan
bentuk dari enzim
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MEMBRAN BOUND ENZYMES
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MEMBRAN BOUND ENZYMES
Nicotinic Recetor
• 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
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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)
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DESAIN AGONIS –
BINDING GROUP• Senyawa dengan struktur yang berbeda,
namun memiliki kelompok ikatan yang
diperlukan untuk berinteraksi dengan
reseptor potensial menjadi agonis.
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DESAIN AGONIS –
BINDING GROUP
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DESAIN AGONIS –
POSISI IKATANThe 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
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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
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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)
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DESAIN ANTAGONIS
• Senyawa antagonis : menghambat agonis untukberikatan sehingga tidak mengaktifkan reseptor
• dua jenis antagonis, yaitu :
1.Antagonis yang bekerja pada binding site2.Antagonis yang bekerja diluar binding site
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DESAIN ANTAGONIS - BS
design a drug that is the right shape to bind to the
receptor binding site, but which either fails to changethe shape of the binding site or distorts it in the
wrong way
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DESAIN ANTAGONIS - BS
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DESAIN ANTAGONIS - BS
Therefore, the molecule acts as an antagonist; it binds to the
receptor, but fails to activate it
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DESAIN ANTAGONIS - BS
17β-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 thre
amino acids in the binding site, while the
hydrophobic skeleton of the molecule
forms van der Waals and hydrophobic
interactions with other regions
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DESAIN ANTAGONIS - BS
17β-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
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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
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DESAIN ANTAGONIS - dBS
1. Antagonis alosterik
2. Antagonis dengan efek “umbrella”
How do these antagonists work?
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DESAIN ANTAGONIS - dBS
1. Antagonis alosterik
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DESAIN ANTAGONIS - dBS
2. Antagonis dengan efek “umbrella”
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afinity of a drug for a receptor : measure
of how strongly that drug binds to the
receptor.
Effiacy : measure of the maximumbiological 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
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RADIOLIGAND LABELLING
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Potensi dari Agonis dinyatakan denganEC50 yaitu kosentrasi yang menyebabkan
munculnya 50% efek
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DESAIN ANTAGONIS/AGONIS
To sum up, if we know the shape and characteristics
of a receptor binding site then we should be able todesign drugs to act as agonists or antagonists
determining the layout of a receptor binding site is
not as straightforward as it sounds
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GOUT DRUGS :MOLECULAR APPROACH DESIGN
TO INHIBITS THE ACTIVITY OF XANTHINE OXIDASE
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MECHANISM OF DISEASES
metabolic disease that resultsfrom hyperur icemia , an
elevation in the blood of uric
acid, the end-product of purine
degradation
Imbalance between elimination
and production of uric aciduric 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
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PHYSICOCHEMICAL OF URIC ACID
weak acid (pKa = 5.6 – 5.75) at
physiologic pH, most of plasma
uric acid is in the ionizedSolubility is markedly reduced as the
temperature fails, protein binding andother molecule
saturating concentration of
monosodium urate 37ºC is
about 420μmol/L (7 mg/dL)
uric acid is only 1/20 as
soluble as sodium urate
Urate is less soluble at lower temperature,
which may explain the peripheral
distribution of urate crystal deposition
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(Abbas, Robbins, Kumar, Collins, & Cotran, 2005)
PHYSICOCHEMICAL OF URIC ACID
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DRUG TARGET AND MECHANISM
Modify purine metabolism to achieve normalconcentrations of plasma urate
Control Pain
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DRUG TARGET AND MECHANISM
Inhibits one or more enzymes in purine metabolism
Allopurinol, Febuxostat (Xanthine Oxidase Inhibitor)
enhance the excretion of plasma urateProbenecid, Sulfinpyrazone, Losartan, Benzbromarone
(Tubular Reasorbtion Blocker, Uricosoid)
Exogenous of Uricase (Enhance Uric acid Metabolism)
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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
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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
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NEW DRUG DESIGN : XO
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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
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RATIONAL DRUG DESIGN: XO
Based on rational design of the interaction ligand : xanthine
and hypoxanthine
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oxidations occur at the MoOS unit of XO, hypoxanthine must
approach MoOS with its C2 oxidable carbon atom, xanthine with its
C8 carbon atom
RATIONAL DRUG DESIGN: XO
C2 of hypoxanthine must be assumed to be geometricallyequivalent with C8 of xanthine
(center α1)
implies that the six-membered ring of one substrate is geometrically
equivalent with the five-membered ring of the other
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RATIONAL DRUG DESIGN: XO
The distance of α1h - α1x is 0.38, α2h – α3x = 0.57, α2x – α3h
= 0.78, α4h – α4x = 0.69. Where h = hypoxanthine and x =
xantine (Rastelli, Costantino, & Albasini, 1997)
the equivalence of the geometrical centers of the two rings
(centers α2 and α3)
the carbonyl oxygen
O6,(center α4)
there is a complete loss of catalytic activity in purine
analogs in which the carbonyl group is replaced by amethyl (6-methylpurine) and a methoxyl (6-
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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 canform a bound from drug to XO.
1. Geometric center of the rings. The similarity to the substrate of
XO.
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RATIONAL DRUG DESIGN: XO
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RATIONAL DRUG DESIGN: XO
flavonoid