Medicinal chemistry Basics: Receptor II

Medicinal chemistry, Drug Discovery Introduction

1. Receptor structure and function

2. Receptors In biochemistry and pharmacology, a  receptor  is a protein molecule usually found embedded within the plasma membrane surface of a cell that receives chemical signals from outside the cell. What Are these Receptors And what do they do?

3. Receptor activation how does an induced fit happen and what is the significance of the receptor changing shape? messenger fits the binding site of the protein receptor it causes the binding site to change shape

4. A hypothetical receptor and neurotransmitte How does the binding site change shape?

5. Receptor activation Fine balance involved in receptor, messenger binding The bonding forces must be large enough to change the shape of the binding site, but not so strong that the messenger is unable to leave

6. Points to remember Most receptors are membrane-bound proteins that contain an external binding site for hormones or neurotransmitters. Binding results in an induced fi t that changes the receptor conformation . This triggers a series of events that ultimately results in a change in cellular chemistry. Neurotransmitters and hormones do not undergo a reaction when they bind to receptors. They depart the binding site unchanged once they have passed on their message. The interactions that bind a chemical messenger to the binding site must be strong enough to allow the chemical message to be received, but weak enough to allow the messenger to depart.

7. Receptor structure

8. Receptor structure

9. Ion channel receptors The structure of an ion channel. The bold lines show the hydrophilic sides of the channel.

10. Lock-gate mechanism for opening ion channels Rapid response in millisecond S ynaptic transmission of signals between neurons usually involves ion channels. Cationic ion channels Na + , K + , and Ca 2+ ions. Anionic ion channels Cl -

11. Structure of Ion channel Nicotinic cholinergic receptor Dextromethorphan Antitussive Glycine receptor Through Cl - b -Alanine Taurine 2-aminoethanesulfonic acid Strychnine & Caffeine

12. Structure of Ion channel Transverse view of Nicotinic cholinergic receptor , including transmembrane regions. The subunits are arranged such that the second transmembrane region of each subunit faces the Central Pore Of The Ion channel

13. Structure of the four transmembrane (4-TM ) receptor subunit

14. Gating When the receptor binds a ligand, it changes shape which has a knock-on effect on the protein complex , causing the ion channel to open

15. Ligand-gated Opening of the l ock gate in an ion channel

16. Points to remember Receptors controlling ion channels are an integral part of the ion channel. Binding of a messenger induces a change in shape , which results in the rapid opening of the ion channel Receptors controlling ion channels are called ligand-gated ion channel receptors. They consist of five protein subunits with the receptor binding site being present on one or more of the subunits. Binding of a neurotransmitter to an ion channel receptor causes a conformational change in the protein subunits such that the second transmembrane domain of each subunit rotates to open the channel.

17. G-protein-coupled receptors Activation of a G-protein-coupled receptor and G-protein Response in Second In general, GPCR activated by hormones ( enkephalins and endorphin ) and slow-acting neurotransmitters ( acetylcholine, dopamine, histamine, serotonin, glutamate, and noradrenaline )

18. Points to remember Robert J. Lefkowitz Howard Hughes Medical Institute and Duke University Medical Center, Durham, NC, USA and Brian K. Kobilka Stanford University School of Medicine, Stanford, CA, USA "for studies of G-protein–coupled receptors" Today this family is referred to as G-protein–coupled receptors. About a thousand genes code for such receptors, for example, for light, flavour, odour, adrenalin, histamine, dopamine and serotonin. About half of all medications achieve their effect through G-protein– coupled receptors 2012  Nobel Prize in Chemistry  

19. Structure Structure of G-protein-coupled receptors The rhodopsin-like family of G-protein-coupled receptors

20. G-protein-coupled receptors When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a  guanine nucleotide exchange factor  (GEF). The GPCR can then activate an associated  G protein  by exchanging its bound  GDP  for a  GTP . Guanine nucleotide exchange factors  (GEFs) activate monomeric  GTPases  by stimulating the release of  guanosine diphosphate  (GDP) to allow binding of  guanosine triphosphate  (GTP) Signal transduction  at the intracellular domain of  transmembrane receptors , including recognition of taste, smell and light. Protein biosynthesis  (a.k.a.  translation ) at the  ribosome . Control and  differentiation  during  cell division . Translocation  of  proteins  through  membranes . Transport of  vesicles  within the  cell . ( GTPases control assembly of vesicle coats.) GTPase-Activating Proteins

21. G-protein-coupled receptors Muscarinic acetylcholine receptors , or  mAChRs , are  acetylcholine receptors  that form  G protein-receptor complexes  in the  cell membranes  of certain  neurons [1]  and other  cells M1- to M5 M1 - secretion from  salivary glands  and  stomach M2 - slow   heart rate M3 - vasodilation M4 - decreased locomotion M5 -  central nervous system  Atropine  - an antagonist. Carbachol

22. G-protein-coupled receptors The  adrenergic receptors  (or  adrenoceptors ) are a class of  G protein-coupled receptors  that are targets of the  catecholamines , especially  norepinephrine (noradrenaline) and  epinephrine  (adrenaline). Epinephrine Norepinephrine Alfuzosin   is a   alpha-1 blocker  class. As an  antagonist  of the  alpha-1 adrenergic receptor , it works by relaxing the muscles in the  prostate  and  bladder  neck, making it easier to urinate. It is thus used to treat  benign prostatic hyperplasia  

23. G-protein-coupled receptors Opioid receptors  are a group of inhibitory  G protein-coupled receptors  with  opioids  as  ligands. The   endogenous  opioids are  dynorphins ,  enkephalins ,  endorphins ,  endomorphins   and nociceptin .  Brain, Spinal cord and in digestive track   δ- opioid receptor Leu-enkephalin Met- enkephalin Deltorphins Norbuprenorphin   μ-opioid ,  δ-opioid , and  nociceptin receptor   full agonist Antagonists Agonists Buprenorphine Trazodone delta ( δ) kappa ( κ) mu ( μ) Nociceptin receptor analgesia antidepressant  effects convulsant  effects physical dependence μ-opioid receptor-mediated respiratory depression

24. G-protein-coupled receptors There are two principal signal transduction pathways involving the G protein–coupled receptors : the  cAMP  signal pathway and the  phosphatidylinositol  signal pathway Class A (or 1) ( Rhodopsin-like ) Class B (or 2) ( Secretin receptor family ) Class C  (or 3) ( Metabotropic glutamate /pheromone) Class D (or 4) ( Fungal mating pheromone receptors ) Class E (or 5) ( Cyclic AMP receptors ) Class F (or 6) ( Frizzled / Smoothened )

25. Glutamic acid, GABA, noradrenaline, dopamine , acetylcholine, serotonin, prostaglandins, adenosine , endogenous opioids, angiotensin, bradykinin, and thrombin Considering the structural variety of the chemical messengers involved, it is remarkable that the overall structures of the G-protein-coupled receptors are so similar. the amino acid sequences of the receptors vary quite significantly. This implies that these receptors have evolved over millions of years from an ancient common ancestral protein

26. G-protein-coupled receptors activate signal proteins called G-proteins . Binding of a messenger results in the opening of a binding site for the signal protein. The latter binds and fragments , with one of the subunits departing to activate a membrane-bound enzyme The G-protein-coupled receptors are membrane-bound proteins with seven transmembrane sections. The C -terminal chain lies within the cell and the N -terminal chain is extracellular. The location of the binding site differs between different G-protein-coupled receptors The rhodopsin-like family of G-protein-coupled receptors includes many receptors that are targets for currently important drugs . Receptor types and subtypes recognize the same chemical messenger , but have structural differences, making it possible to design drugs that are selective for one type (or subtype) of receptor over another. Receptor subtypes can arise from divergent or convergent evolution .

27. Kinase-linked receptors Kinase-linked receptors are a superfamily of receptors which activate enzymes directly and do not require a G-protein

28. Kinase-linked receptors Strcture Structure of tyrosine kinase receptors

29. Activation mechanism for tyrosine kinase receptors Activation mechanism for the epidermal growth factor (EGF) receptor

30. Ligand binding and activation of the insulin receptor. Zn

31. Activation of the growth hormone (GH) receptor

32. Kinase-linked receptors are receptors which are directly linked to kinase enzymes. Messenger binding results in the opening of the kinase-active site, allowing a catalytic reaction to take place. Tyrosine kinase receptors have an extracellular binding site for a chemical messenger and an intracellular enzymatic active site which catalyses the phosphorylation of tyrosine residues in protein substrates. The insulin receptor is a preformed heterotetrameric structure which acts as a tyrosine kinase receptor. The growth hormone receptor dimerizes on binding its ligand, then binds and activates tyrosine kinase enzymes from the cytoplasm .

33. Intracellular receptors nuclear hormone receptors or nuclear transcription factors

34. From messenger to control of gene transcription.

35. Evolutionary tree of G-protein-coupled receptors. The human beta-2 adrenergic receptor in complex with the partial inverse agonist carazolol