Receptor ppt

Drug receptor

1. By P r of. Rakesh D. Amrutkar Head of Department , Pharmaceutical Chemistry Mahatma Gandhi Vidyamandir’s Samajshri Prashantdada Hiray College of Pharmacy, Malegaon. Drug Receptor 1

2. 2 HISTORY First postulated by John Langley (1878) Established after his experiments using nicotine and curare analogues on muscle contraction. Furthered by Paul Ehrlich (1845-1945) Demonstrated that stereoselectivity was essential in drug-receptor signaling.

3. PAUL EHRLICH 1845-1945 Drugs cannot act unless they are bound to receptors 3

4. RECEPTOR: A receptor is the specific chemical constituent of the cell with which a drug interacts to produce it’s pharmacological effects. Some receptor sites have been identified with specific parts of proteins and nucleic acids. In most cases, the chemical nature of the receptor site remains doubtful. Any cellular macromolecule that a drug binds to initiate its effects. 4

5. LIGANDS Neurotransmitters Drugs 5

6. Chemical Messengers Neurotransmitters : Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve. Usually short lived and responsible for messages between individual cells. Hormones : Chemicals released from cells or glands and which travel some distance to bind with receptors on target cells throughout the body. Chemical messengers ‘switch on’ receptors without undergoing a reaction 6

7. 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. Once bound to the receptor an agonist activates or enhances cellular activity. 7

8. Ligand-Receptors Binding Binding site specific point of ligand & receptor Affinity attraction physical & electrical fit NT or drug binds to receptor  or  activity of neuron excite or inhibit Drugs mimic or block NT message 8

9. Lock & Key Model Receptor changes shape Excitation or Inhibition.. Determined by nature of receptor receptor subtypes NOT NT NT binds to receptor NT = key Receptor = lock 9

10. Receptor A NT Ligand binds to receptor 10

11. Receptor B Receptor A Same NT can bind to different Receptor But different part of NT NT 11

12. Receptor B Receptor A Same NT can bind to different Receptor But different part of NT NT 12

13. Receptor B Receptor A NT Specificity of Drugs Drug A Drug B 13

14. Structure-activity relationship NT fits receptor site key & lock Change structure of drug... change its affinity increase or decrease may bind to different receptor 14

15. Structure and function of receptors Globular proteins acting as a cell’s ‘letter boxes’ Located mostly in the cell membrane Receive messages from chemical messengers coming from other cells Transmit a message into the cell leading to a cellular effect Different receptors specific for different chemical messengers Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengers 15

16. Cell Nerve Messenger Signal Receptor Nerve Nucleus Cell Response 16

17. Nerve 1 Nerve 2 Hormone Blood supply Neurotransmitters 17

18. Mechanism Receptors contain a binding site (hollow or cleft in the receptor surface) that is recognised by the chemical messenger Binding of the messenger involves intermolecular bonds Binding results in an induced fit of the receptor protein Change in receptor shape results in a ‘domino’ effect Domino effect is known as Signal Transduction, leading to a chemical signal being received inside the cell Chemical messenger does not enter the cell. It departs the receptor unchanged and is not permanently bound 18

19. Mechanism Cell Membrane Cell Receptor Messenger message Induced fit Cell Receptor Messenger Message Cell Messenger Receptor 19

20. ENZYME Binding site of Receptor A hydrophobic hollow or cleft on the receptor surface - equivalent to the active site of an enzyme Accepts and binds a chemical messenger Contains amino acids which bind the messenger No reaction or catalysis takes place Binding site Binding site 20

21. The Binding Site 21

22. Messenger Binding Binding site is nearly the correct shape for the messenger Binding alters the shape of the receptor (induced fit) Altered receptor shape leads to further effects - signal transduction Messenger Induced fit M 22

23. Ionic H-bonding van der Waals Bonding forces Example: Receptor Binding site vdw interaction ionic bond H-bond Phe Ser O H Asp CO 2 Messenger B inding 23

24. Substrate B inding Induced fit - Binding site alters shape to maximize intermolecular bonding Bonding forces Intermolecular bonds not optimum length for maximum binding strength Intermolecular bond lengths optimised Phe Ser O H Asp CO 2 Induced Fit Phe Ser O H Asp CO 2 24

25. Overall process of receptor/messenger interaction M M E R Binding interactions must be: - strong enough to hold the messenger sufficiently long for signal transduction to take place - weak enough to allow the messenger to depart Implies a fine balance Drug design - designing molecules with stronger binding interactions results in drugs that block the binding site - antagonists R M E R Signal transduction 25

26. HOW DRUGS ACT l. Enzyme Inhibition: Drugs act within the cell by modifying normal biochemical reactions. Enzyme inhibition may be reversible or non reversible; competitive or non-competitive. 2. Drug-Receptor Interaction: Drugs act on the cell membrane by physical and/or chemical interactions-usually through specific drug receptor sites known to be located on the membrane. Some receptor sites have been identified with specific parts of proteins and nucleic acids. In most cases, the chemical nature of the receptor site remains obscure. 3. Non-specific Interactions: Drugs act exclusively by physical means outside of cells. These sites include external surfaces of skin and gastro-intestinal tract. Drugs also act outside of cell membranes by chemical interactions. Neutralization of stomach acid by antacids is a good example 26

27. Receptor S uperfamilies ION CHANNEL RECEPTORS (Iontropic receptor) G-PROTEIN COUPLED RECEPTORS (Metabotropic R) KINASE LINKED RECEPTORS INTRACELLULAR RECEPTORS MEMBRANE BOUND 27

28. 28 Classes of cell-surface receptors

29. Transverse view (nicotinic receptor) Two ligand binding sites mainly on a -subunits a a g d b Ion channel 2 x a, b, g, d subunits Cell membrane a a d b g Binding sites Ion channel receptors (Ligand gated ion channels) 29

30. Transverse view (glycine receptor) Three ligand binding sites on a -subunits a a b b a Ion channel 3 x a, 2 x b subunits Cell membrane a a a b b Binding sites Ion channel receptors (Ligand gated ion channels) 30

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34. G Protein-Coupled Receptors 7-helices transmembrane receptor 34

35. G protein refers to any protein which binds to GDP or GTP and act as signal transduction. G proteins consist of three different subunits ( , ,  - subunit ) .  -subunit carries GTPase activity, binding and hydrolysis of GTP. G protein ( Guanylate binding protein) 35

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37. G protein-gated Ion Channels R G GDP 37

38. G protein-gated Ion Channels R G GTP Pore 38

39. Second Messenger Effects Modulate phosphorylation activation of processes Protein Kinases   Protein Phosphatases   Modulate gene expression transcriptional factors DNA  RNA  Proteins e.g., -R up- or down-regulation ~ 39

40. G protein: Protein Phosphorylation R G GTP A C GDP * PKA 40

41. G protein: Protein Phosphorylation R A C PKA G GTP ATP cAMP P Pore 41

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