DRUG - RECEPTOR

KULIAH 3

ENZYME- RECEPTOR

• Enzyme: A protein (or protein-based molecule) that speeds up a chemical reaction in a living organism.

• An enzyme acts as catalyst for specific chemical reactions, converting a specific set of reactants (called substrates) into specific products.

• Without enzymes, life as we know it would not exist.

• enzyme : Symbol E• a protein that catalyzes chemical reactions of other

substances without itself being destroyed or altered upon completion of the reactions.

• Enzymes are divided into six main groups, according to the reactions they catalyze :

• oxidoreductases, • transferases, • hydrolases,• lyases, • isomerases, and • ligases.

• llosteric enzyme one whose catalytic activity is altered by binding of specific ligands at sites other than the substrate binding site.

• brancher enzyme , branching enzyme 1,4-α-glucan branching enzyme: an enzyme that catalyzes the creation of branch points in glycogen (in plants, amylopectin); deficiency causes glycogen storage disease type IV.

• constitutive enzyme one produced constantly, irrespective of environmental conditions or demand.

• debrancher enzyme , debranching enzyme • 1. amylo-1,6-glucosidase.• 2. any enzyme removing branches from macromolecules,

usually polysaccharides, by cleaving at branch points.

• induced enzyme , inducible enzyme one whose production can be stimulated by another compound, often a substrate or a structurally related molecule.

• proteolytic enzyme peptidase.• repressible enzyme one whose rate of

production is decreased as the concentration of certain metabolites is increased.

• respiratory enzyme one that is part of an electron transport (respiratory) chain.

Enzyme Composition• Enzymes can have molecular weights ranging from

about 10,000 to over 1 million. A small number of enzymes are not proteins, but consist of small catalytic RNA molecules.

• Often, enzymes are multiprotein complexes made up of a number of individual protein subunits.

• Many enzymes catalyze reactions without help, but some require an additional non-protein component called a co-factor. Co-factors may be inorganic ions such as Fe2+, Mg2+, Mn2+, or Zn2+, or consist of organic or metalloorganic molecules knowns as co-enzymes.

• Alcohol dehydrogenase: an oxidoreductase converting alcohols to aldehydes/ ketones.

• Aminotransferases: transferases catalyzing the amino acid degradation by removing amino groups.

• Glucose-6-phosphatase: a hydrolase that removes the phosphate group from glucose-6-phosphate, leaving glucose and H3PO4.

• Pyruvate decarboxylase: a lyase that removes CO2 from pyruvate.

• Ribulose phosphate epimerase: an isomerase that catalyzes the interconversion of ribulose-5-phosphate and xylulose-5-phosphate.

• Hexokinase: a ligase that catalyzes the interconversion of glucose and ATP with glucose-6-phosphate and ADP.

Asam nukleat

• Nucleic acid structure refers to the structure of nucleic acids such as DNA and RNA It is often divided into four different levels:

• Struktur primer• S. sekunder• S tersier• S. Kuarterner

• Nucleic acids consist of a chain of linked units called nucleotides.

• Each nucleotide consists of three subunits: a phosphate group and a sugar (ribose in the case of RNA, deoxyribose in DNA) make up the backbone of the nucleic acid strand, and attached to the sugar is one of a set of nucleobases.

• The nucleobases are important in base pairing of strands to form higher-level secondary and tertiary structure such as the famed double helix.

• RNA

Sekunder

Tersier

Kuarterner• The quaternary structure of a nucleic acid refers to the

interactions between separate nucleic acid molecules, or between nucleic acid molecules and proteins.

• The concept is analogous to protein quaternary structure, but as the analogy is not perfect, the term is used to refer to a number of different concepts in nucleic acids and is less commonly encountered.

• Quaternary structure can refer to the higher-level organization of DNA in chromatin,[1] including its interactions with histones.

• It may also refer to the interactions between separate RNA units in the ribosome[2][3] or spliceosome.

Receptor in biology• In biochemistry, a receptor is a protein molecule,

embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling (or "signal") molecule may attach.

• A molecule which binds to a receptor is called a "ligand," and may be a peptide (such as a neurotransmitter), a hormone, a pharmaceutical drug, or a toxin, and when such binding occurs, the receptor goes into a conformational change which ordinarily initiates a cellular response.

• Some ligands merely block receptors without inducing any response (e.g. antagonists). Ligand-induced changes in receptors result in physiological changes which constitute the biological activity of the ligands.

• In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds a specific substance. There are many receptors. There is a receptor for (insulin; there is a receptor for low-density lipoproteins (LDL); etc.

• To take an example, the receptor for substance P, a molecule that acts as a messenger for the sensation of pain, is a unique harbor on the cell surface where substance P docks. Without this receptor, substance P cannot dock and cannot deliver its message of pain.

• Variant forms of nuclear hormone receptors mediate processes such as cholesterol metabolism and fatty acid production.

• Some hormone receptors are implicated in diseases such as diabetes and certain types of cancer. A receptor called PXR appears to jump-start the body's response to unfamiliar chemicals and may be involved in drug-drug interactions.

• In neurology, a terminal of a sensory nerve that receives and responds to stimuli.

• In Biochemistry, a molecular structure or site on the surface or interior of a cell that binds with substances such as hormones, antigens, drugs, or neurotransmitters

• A structure or site, found on the surface of a cell or within a cell, that can bind to a hormone, antigen, or other chemical substance and thereby begin a change in the cell.

• For example, when a mast cell within the body encounters an allergen, specialized receptors on the mast cell bind to the allergen, resulting in the release of histamine by the mast cell.

• The histamine then binds to histamine receptors in other cells of the body, which initiate the response known as inflammation as well as other responses.

• In this way, the symptoms of an allergic reaction are produced.

• Antihistamine drugs work by preventing the binding of histamine to histamine receptors.

PharmacologyA cellular macromolecule, or an assembly of macromolecules,that is concerned directly and specifically inchemical signaling between and within cells.

Combination of a hormone, neurotransmitter, drug, or intracellularmessenger with its receptor(s) initiates a change incell function.

Thus NC-IUPHAR does not classify simplebinding sites, without function (although truncated proteinswithout signaling function may be designated assuch, to avoid confusion).

A receptor may consist of several proteins, called subunits. In some cases the large number of combinatorial possibilities for assembly of multiple subunits may require NC-IUPHAR to use an interim nomenclature based on the individual subunits (Spedding et al., 2002)Receptor: Any cellular macromolecule that a drug binds to initiate its effects.Drug: A chemical substance that interacts with a biological system to produce a physiologic effect.

• All drugs are chemicals but not all chemicals are drugs.

• The ability to bind to a receptor is mediated by the chemical structure of the drug that allows it to interact with complementary surfaces on the receptor.

• Drugs that interact with receptors can be classified as being either agonists or antagonists.

• Once bound to the receptor an agonist activates or enhances cellular activity.

• Examples of agonist action are drugs that bind to beta receptors in the heart and increase the force of myocardial contraction or drugs that bind to alpha receptors on blood vessels to increase blood pressure. The binding of the agonist often triggers a series of biochemical events that ultimately leads to the alteration in function.

• The biochemicals that initiate these changes are referred to as second messengers.

• Antagonists have the ability to bind to the receptor but do not initiate a change in cellular function. Because they occupy the receptor, they can prevent the binding and the action of agonists. Hence the term antagonist.

• Antagonists are also referred to as blockers.

INTERAKSI OBAT-RESEPTOR• Interaksi obat/drug dengan reseptor akan menimbulkan efek

biologis• Efek agonis• Efek antagonis

• Mekanisme timbulnya respons ada 6 teori:• 1. Teori Klasik• 2. Teori kependudukan• 3. Teori kecepatan• 4. Teori kessuaian terimbas• 5. Teori gangguan molekul• 6. Teori pendudukan aktivasi

1. Teori klasik• Crum, Brown dan Fraser: 1869, aktivitas

biologis suatu senyawa merupakan fungsi struktur kimia dan tempat obat berinteraksi

• Langley: 1878, mengungkapkan konsep reseptor• Erlich: 1907, obat tak berefek bila tdk tidak

terikat pada reseptor yang khas, atau sisi reseptor dan saling mengisi

2. Teori Pendudukan• Clark, 1926 : suatu obat akan menempati sisi

reseptor dan diberikan dalam jumlah banyak agar efektif selama proses pembentukan kompleks

• O + R membentuk OR• O + R afn Kompleks OR efikasi Respons

biologis• Respons (+): seny. Agonis, afn >, akt intrsik 1• Respons (-): seny. Antagonis, afn >, akt intrisik 0• Afinitas: kemampuan obat u mengikat reseptor• Aktintrisik: kemampuan obat u memulai timbulnya

respons biologis

• An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance.

• Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist.

• Receptors can be activated or inactivated by either endogenous (such as hormones and neurotransmitters) or exogenous (such as drugs) agonists and antagonists, resulting in the stimulation or inhibition of a biological response.

• A physiological agonist is a substance that creates the same bodily responses but does not bind to the same receptor.

• An endogenous agonist for a particular receptor is a compound naturally produced by the body that binds to and activates that receptor.

• For example, the endogenous agonist for serotonin receptors is serotonin, and the endogenous agonist for dopamine receptors is dopamine.[1]

Efficacy spectrum• A superagonist is a compound that is capable of producing a

greater maximal response than the endogenous agonist for the target receptor, and thus has an efficacy of more than 100%.

• This does not necessarily mean that it is more potent than the endogenous agonist, but is rather a comparison of the maximum possible response that can be produced inside the cell following receptor binding.

• Full agonists bind (have affinity for) and activate a receptor, displaying full efficacy at that receptor. One example of a drug that acts as a full agonist is isoproterenol, which mimics the action of adrenaline at β adrenoreceptors.

• Another example is morphine, which mimics the actions of endorphins at μ-opioid receptors throughout the central nervous system.

• Partial agonists (such as buspirone, aripiprazole, buprenorphine, or norclozapine) also bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. One study of benzodiazepine active sedative hypnotics found that partial agonists have just under half the strength of full agonists.[2] Partial agonists such as abecarnil have demonstrated a reduced rate and reduced severity of dependence and withdrawal syndromes.[3]

• An inverse agonist is an agent that binds to the same receptor binding-site as an agonist for that receptor and reverses constitutive activity of receptors. Inverse agonists exert the opposite pharmacological effect of a receptor agonist.

3. Teori kecepatan• Paton: 1961, efek biologis setara dengan kecep

kombinasi OR, bukan jumlah R yang diduduki• Kerja obat ditentukan dgn kecepatan asosiasi dan

kecepatan disosiasi kompleks OR bukan pembentukan OR

• O + R assosiasi kompleks OR dissosiasi

Respons biologis

• Senyawa agonis, kecepatan assosiasi dan disosiasi besar

• Senyawa antagonis, kecepatan asosiasi besar tp dissosiasinya kecil

• Seny agonis parsial jika kecepatan asosiasi dan dissosiasi tidak maksimal

• Fakta: senyawa mempunyai efek singkat, karena jumlah reseptor yang diduduki sedikit, kecepatan penggabungan maksimum, dan rangsangan singkat

4. Teori kesesuaian terimbas• Koshland, 1955, kombinasi enzim dan substrat

akan terjadi perubahan konformsi struktur enzim, perubahan orientasi gugus aktif enzim

• E + S ES Resp Bio

5. Teori gangguan molekul• Belleau, 1964, interaksi mikromolekul dan

makromolekul menyebabkan terjadi perub konformasi reseptor:

• 1. Gangguan konformasi khas (SCP)• 2. Gangguan konformasi tidak khas (NSCP)

• Obat agonis, punya akt intrisik, mengubah reseptor menjadi bentuk SCP

• Obat antagonis, tdk punya akt intrisik, mengubah reseptor, menjadi NSCP, efek pemblokan,

• Sbg penunjang adanya ikatan hidrofobik

6. Teori Pendudukan Aktivasi• Ariens dan Rodrigues, sebelum berinteraksi dgn

obat, eseptorr berada dalam kesetimbangan dinamik yaitu dalam bentuk R dan R*

• R dalam bentuk istirahat, tdk dpt menunjang efek biologis

• R* bentuk yang teraktifkan, dpt menunjang efek biologis

• agonis

• R R*• antagonis

• Senyawa agonis: kesetimbangan kearah R*• Senyawa antagonis: kesetimbangan ke arah R• Senyawa agonis parsial: terjadi bentuk R dan R*• Senyawa agonis biasanya sangat polar,

distabilkan oleh reseptor polar shg kesetimb kearah R* yg lebih hiddrofil

• Senyawa antagonis , memp gugus2 yang hidrofob, distabilkan oleh reseptor yang hidrofob, shg menggeser kesetimbangan ke arah R