Target Kerja Obat (Reseptor)

7/23/2019 Target Kerja Obat (Reseptor)

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DRUG TARGET



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.



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 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



Transpor ProteinStruktur 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




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



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 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



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 untukberikatan sehingga tidak mengaktifkan reseptor

• dua jenis antagonis, yaitu :

1.Antagonis yang bekerja pada binding site2.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 changethe shape of the binding site or distorts it in the

wrong way




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

receptor, but fails to activate it




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




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




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

1. Antagonis alosterik

2. Antagonis dengan efek “umbrella”

How do these antagonists work?




1. Antagonis alosterik




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 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



RADIOLIGAND LABELLING



Potensi dari Agonis dinyatakan denganEC50 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 todesign 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 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



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



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

PHYSICOCHEMICAL OF URIC ACID



DRUG TARGET AND MECHANISM

Modify purine metabolism to achieve normalconcentrations 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 urateProbenecid, 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




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




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



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 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




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-




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.




flavonoid

Target Kerja Obat (Reseptor)

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