Target Kerja Obat (Reseptor)

download Target Kerja Obat (Reseptor)

of 49

  • date post

    18-Feb-2018
  • Category

    Documents

  • view

    222
  • download

    0

Embed Size (px)

Transcript of Target Kerja Obat (Reseptor)

  • 7/23/2019 Target Kerja Obat (Reseptor)

    1/49

    DRUG TARGET

  • 7/23/2019 Target Kerja Obat (Reseptor)

    2/49

    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.

  • 7/23/2019 Target Kerja Obat (Reseptor)

    3/49

  • 7/23/2019 Target Kerja Obat (Reseptor)

    4/49

    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)

  • 7/23/2019 Target Kerja Obat (Reseptor)

    5/49

    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

  • 7/23/2019 Target Kerja Obat (Reseptor)

    6/49

    Transpor ProteinStruktur protein ion channels.

  • 7/23/2019 Target Kerja Obat (Reseptor)

    7/49

    LOCK GATE MECHANISM

    pembawa pesan terikat, perubahan bentuk reseptor

    menyebabkan lock gate terbuka dan ion dapat masuk, dan

    sebaliknya.

  • 7/23/2019 Target Kerja Obat (Reseptor)

    8/49

    MEMBRAN BOUND ENZYMES

    Ketika protein reseptor terikat pada

    neurotransmiternya bentuk reseptor

    berubah dan menyebabkan perubahan

    bentuk dari enzim

  • 7/23/2019 Target Kerja Obat (Reseptor)

    9/49

    MEMBRAN BOUND ENZYMES

  • 7/23/2019 Target Kerja Obat (Reseptor)

    10/49

    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 perreceptor protein

  • 7/23/2019 Target Kerja Obat (Reseptor)

    11/49

  • 7/23/2019 Target Kerja Obat (Reseptor)

    12/49

    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)

  • 7/23/2019 Target Kerja Obat (Reseptor)

    13/49

    DESAIN AGONIS

    BINDING GROUP Senyawa dengan struktur yang berbeda,

    namun memiliki kelompok ikatan yang

    diperlukan untuk berinteraksi dengan

    reseptor potensial menjadi agonis.

  • 7/23/2019 Target Kerja Obat (Reseptor)

    14/49

    DESAIN AGONIS

    BINDING GROUP

  • 7/23/2019 Target Kerja Obat (Reseptor)

    15/49

    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

  • 7/23/2019 Target Kerja Obat (Reseptor)

    16/49

    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

  • 7/23/2019 Target Kerja Obat (Reseptor)

    17/49

    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)

  • 7/23/2019 Target Kerja Obat (Reseptor)

    18/49

    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 diluarbinding site

  • 7/23/2019 Target Kerja Obat (Reseptor)

    19/49

    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

  • 7/23/2019 Target Kerja Obat (Reseptor)

    20/49

    DESAIN ANTAGONIS - BS

  • 7/23/2019 Target Kerja Obat (Reseptor)

    21/49

    DESAIN ANTAGONIS - BS

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

    receptor, but fails to activate it

  • 7/23/2019 Target Kerja Obat (Reseptor)

    22/49

    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 thre

    amino acids in the binding site, while the

    hydrophobic skeleton of the molecule

    forms van der Waals and hydrophobic

    interactions with other regions

  • 7/23/2019 Target Kerja Obat (Reseptor)

    23/49

    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

  • 7/23/2019 Target Kerja Obat (Reseptor)

    24/49

    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

  • 7/23/2019 Target Kerja Obat (Reseptor)

    25/49

    DESAIN ANTAGONIS - dBS

    1. Antagonis alosterik

    2. Antagonis dengan efekumbrella

    How do these antagonists work?

  • 7/23/2019 Target Kerja Obat (Reseptor)

    26/49

    DESAIN ANTAGONIS - dBS

    1. Antagonis alosterik

  • 7/23/2019 Target Kerja Obat (Reseptor)

    27/49

    DESAIN ANTAGONIS - dBS

    2. Antagonis dengan efekumbrella

  • 7/23/2019 Target Kerja Obat (Reseptor)

    28/49

    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

  • 7/23/2019 Target Kerja Obat (Reseptor)

    29/49

    RADIOLIGAND LABELLING

  • 7/23/2019 Target Kerja Obat (Reseptor)

    30/49

    Potensi dari Agonis dinyatakan denganEC50 yaitu kosentrasi yang menyebabkan

    munculnya 50% efek

  • 7/23/2019 Target Kerja Obat (Reseptor)

    31/49

  • 7/23/2019 Target Kerja Obat (Reseptor)

    32/49

  • 7/23/2019 Target Kerja Obat (Reseptor)

    33/49

    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

  • 7/23/2019 Target Kerja Obat (Reseptor)

    34/49

    GOUT DRUGS :MOLECULAR APPROACH DESIGN

    TO INHIBITS THE ACTIVITY OF XANTHINE OXIDASE

  • 7/23/2019 Target Kerja Obat (Reseptor)

    35/49

    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

  • 7/23/2019 Target Kerja Obat (Reseptor)

    36/49

    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 37C is

    about 420mol/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

  • 7/23/2019 Target Kerja Obat (Reseptor)

    37/49

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

    PHYSICOCHEMICAL OF URIC ACID

  • 7/23/2019 Target Kerja Obat (Reseptor)

    38/49

    DRUG TARGET AND MECHANISM

    Modify purine metabolism to achieve normalconcentrations of plasma urate

    Control Pain

  • 7/23/2019 Target Kerja Obat (Reseptor)

    39/49

    DRUG TARGET AND MECHANISM

    Inhibits one or more enzymes in purine metabolism

    Allopurinol, Febuxostat (Xanthine Oxidase Inhibitor)

    enhance the excretion of plasma urateProbeneci