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Drugs acting at miscellaneous targets
Patrick: An Introduction to Medicinal Chemistry 6e Chapter 10 Drugs acting at miscellaneous targets modified
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MISCELLANEOUS DRUG TARGETS
Transport Proteins Structural Proteins Biosynthetic Building Blocks Protein synthesis - chain terminators Protein-Protein Interactions Cell Membrane Lipids Carbohydrates Antigens and Antibodies
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1. Agents blocking Transport Proteins
Notes Agents binding to transport proteins prevent re-uptake of neurotransmitters (e.g. dopamine, serotonin, noradrenaline) Results in increased levels of affected neurotransmitters The resulting effect is similar to using an agonist for neurotransmitters Reuptake inhibitor for dopamine in central nervous system Causes euphoric effects Reuptake inhibitor of noradrenaline in the peripheral system Suppresses hunger Cocaine
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1. Agents blocking Transport Proteins
Examples Fluoxetine (Prozac) Selective serotonin reuptake inhibitor (SSRI) Used as an antidepressant Desipramine Example of a tricyclic antidepressant Non-selective reuptake inhibitor for noradrenaline Principle treatment for depression from modified
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1. Agents blocking Transport Proteins
Examples Reboxetine Selective noradrenaline reuptake inhibitor (SNRI) Used as an antidepressant since 2003 Venlafaxine Dual noradrenaline and serotonin reuptake inhibitor Used as an antidepressant modified
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1. Agents blocking Transport Proteins
Examples Bupropion (Zyban) Reuptake inhibitor for noradrenaline and dopamine Used as an antidepressant and to aid smoking cessation Sibutramine Reuptake inhibitor of serotonin, noradrenaline, and dopamine Used as an anti-obesity agent modified
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Methylphenidate (Ritalin)
1. Agents blocking Transport Proteins Examples Methylphenidate (Ritalin) Reuptake inhibitor for noradrenaline and dopamine Used to treat attention deficit hyperactivity disorder
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2. Agents acting on Structural Proteins
2.1 Agent binding to a viral structural protein Cell entry by HIV Virus gp41 Host cell Virus Helical folding Fusion Host cell Blocking fusion Virus gp41 Virus Host cell Enfuvirtide Fusion blocked Host cell Notes gp41 helices fold over on each other to form twice as many helices, which are half as long – draws virus and host cell together leading to fusion Enfuvirtide is a polypeptide containing 36 amino acids Used vs HIV since 2003 Acts as a fusion inhibitor by binding to gp41 and preventing the folding of the helices. Virus and host cell are not pulled together and fusion is blocked
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2. Agents acting on Structural Proteins
2.2 Inhibitors of tubulin polymerisation Colchicine (used vs gout) Vinblastine (anticancer agent) modified
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2. Agents acting on Structural Proteins
2.2 Inhibitors of tubulin depolymerisation Side chain Paclitaxel (Taxol) Oxetane Benzoyl Acetyl Modified Structure refreshed Notes Important anticancer agent isolated from the yew tree Accelerates tubulin polymerisation and stabilises microtubules Cell division cycle halted Binds to tubulin via side chain, acetyl, benzoyl, and oxetane groups
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3. Agents acting on Biosynthetic Building Blocks
Vancomycin Peptide chain modifed Notes Important antibacterial agent Caps the building block used in synthesis of bacterial cell wall Contains a peptide chain which forms H-bonds to the target Vancomycin acts as a ‘receptor’ for the building block
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. . . 3. Agents acting on Biosynthetic Building Blocks Notes
Growing cell wall . Cross-linking Vancomycin . Gly . Transglycosidation NAG Cytoplasm Cell membrane Carrier lipid L-Ala D-Glu L-Lys NAM L-Ala D-Ala D-Ala-D-Ala Amino acid Notes Building block partially constructed in cytoplasm Constructed from a sugar (NAM) and a peptide chain Transported across cell membrane and completed (NAM + glycines) Linked to growing cell wall by enzyme (transglycosidation)
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3. Agents acting on Biosynthetic Building Blocks
Cell membrane Building block Vancomycin Notes Vancomycin binds to peptide chain of building block Caps the building block Disguises building block from transglycosidation enzyme
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4. Chain terminators - protein synthesis
Aminoacyl moiety Aminoacyl-tRNA Puromycin Adenosine modified Notes Puromycin is an antibiotic which stops protein synthesis Acts as a chain terminator during translation Mimics aminoacyl-tRNA molecules used during translation Binds to ribosome instead of an aminoacyl-tRNA
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4. Chain terminators - protein synthesis
tRNA Peptide chain Phosphate Adenine Ribose O H tRNA Phosphate Adenine Ribose P u r o m y c i n N Peptide chain P u r o m y c i n N H 2 modifed Notes Puromycin binds to the ribosome and interacts with the bound t-RNA that has the attached protein chain The protein chain is transferred to puromycin Puromycin departs the ribosome carrying away a stunted protein
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5. Protein-protein binding inhibitors
5.1 Notes Molecules capable of inhibiting protein-protein binding interactions Protein-protein interactions are important in many biochemical mechanisms Interactions sometimes involve a relatively few amino acids on each protein Feasible to design small molecules that mimic these groups on one of the proteins Small molecule should be capable of binding to the other protein and prevent protein-protein interactions Examples already known - drugs interacting with tubulin
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5. Protein-protein binding inhibitors
5.2 Examples Tirofibin Notes Thought to mimic a tripeptide sequence (Arg-Gly-Asp) found in fibrinogen Binds to an integrin that normally binds fibrinogen Blocks interaction between integrin and fibrinogen Used as an anticoagulant
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5. Protein-protein binding inhibitors
5.3 Nutlins Bromophenyl groups Nutlin-2 p53 Protein M e H N Phe-19 Trp-23 Leu-26 Ethoxy group Notes Nutlin-2 mimics three amino acids (Leu, Trp, Phe) found in the protein p53 The bromophenyl groups and the ethoxy group in nutlin-2 mimic the three residues of p53
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5. Protein-protein binding inhibitors
5.3 Nutlins p53 acts to restrict cell growth or produce cell death in damaged cells or cells under stress (e.g. cancer cells) p53 is normally suppressed by interaction with another protein (MDM2) Some cancer cells have excess MDM2 which prevents p53 acting The three residues in p53 are like fingers which fit into three binding pockets in the MDM2 protein Nutlins mimic these interactions and bind to the excess MDM2, allowing p53 to act Nutlins have potential as anticancer agents modified
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5. Protein-protein binding inhibitors
5.4 Terphenyl-based structures Scaffold ortho substituent meta = alpha-helix R1 R4 R7 Notes Scaffold designed to mimic backbone of an alpha-helix Substituents mimic amino acid residues at 1st, 4th and 7th residues of an alpha-helix Structure shown acts as an antagonist for calmodulin Varying substituents varies the target protein
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5. Protein-protein binding inhibitors
5.4 Terphenyl-based structures Structure shown binds to the protein BCl-xL BCl-xLplays an important role in suppressing apoptosis Terphenyls may be useful in promoting apoptosis in tumour cells
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5. Protein-protein binding inhibitors
5.5 Targeting transcription factor-coactivator interactions Target Sur-2 protein Interaction between the ESX transcription factor and the co-activator protein Sur-2 involves an eight-amino acid a-helix of ESX Trp forms a particularly important interaction
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5. Protein-protein binding inhibitors
5.5 Targeting transcription factor-coactivator interactions Lead compound Urea Adamanolol Isopropyl group Adamantane ring Indole ring Notes Search for a lead compound containing an indole ring to mimic Trp Lead compound = adamanolol Adamantane ring thought to mimic Ile and Leu residues Isopropyl group important for enforcing the shape of the molecule
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5. Protein-protein binding inhibitors
5.5 Targeting transcription factor-coactivator interactions 'Handle' Wrenchnolol Wrenchnolol Drug optimisation 'Jaws' Notes More active and water soluble Two hydrophobic jaws and a polar handle Amphiphilic molecule mimicking amphiphilic alpha helix Non-polar components clustered on one face of the molecule The jaws mimic Try, Leu and Ile
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6. Agents interacting with cell membrane lipids
Plasma membrane Nucleus Phospholipid bilayer Cytoplasm
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6. Agents interacting with cell membrane lipids
Exterior Interior High [Na+] High [K+] Phospholipid Bilayer
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6. Agents interacting with cell membrane lipids
Drugs acting on cell membrane lipids - Anaesthetics and some antibiotics Action of amphotericin B (antifungal agent) - builds tunnels through membrane and drains cell Hydrophilic Hydrophobic region modified
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6. Agents interacting with cell membrane lipids
Tunnel Polar tunnel formed Escape route for ions modified
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6. Agents interacting with cell membrane lipids
Gramicidin A Val-Gly-Ala-Leu-Ala-Val-Val-Val-Trp-Leu-Trp-Leu-Trp-Leu-Trp-NH-CH2-CH2-OH Notes Peptide antibiotic thought to form a helix in the cell membrane Two helices aligned end to end to form an ‘escape tunnel’ Hydrophobic exterior interacts with cell membrane lipids Hydrophilic interior allows uncontrolled passage of ions Ions Modified Diagram of cell redone Cell
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6. Agents interacting with cell membrane lipids
Magainins Polypeptide antibiotics containing 23 amino acids Form helices in the cell membrane Interact with polar head groups of cell membrane lipids Create ‘wormholes’ that disrupt permeability Magainin helix Cell membrane Cell membrane Cell membrane
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6. Agents interacting with cell membrane lipids
‘Killer nanotubes’ Synthetic cyclic peptides Self assemble in bacterial cell membranes to form nanotubes Alternating L- and D- amino acids Amide groups perpendicular to plane of the cyclic peptide Allows H-bonding between each layer of cyclic peptide Residues sticking out in the same plane do not interfere with layering Lysine aids selectivity for bacterial cells which have a negatively charged surface – the lysine side chain is positively charged. Self assembly R ‘Killer’ nanotube modified Cyclic peptide R Stacking of cyclic peptides through H-bonding
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6. Agents interacting with cell membrane lipids
Valinomycin D-Valine L-Lactate L-Valine D-Hyi Notes Cyclic structure with alternating ester and amide links Hydrophobic residues on exterior Polar carbonyl groups in interior
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6. Agents interacting with cell membrane lipids
Mechanism of action Acts as an ion carrier Hydrophobic groups on exterior interact with membrane lipids Carbonyl groups interact with potassium ion Allows uncontrolled escape of potassium ions from cell K+ Exterior Cytoplasm Cell membrane K+ Valinomycin K+
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7. Agents acting on carbohydrates
Carbohydrates play important roles in cell recognition, regulation and growth Potential targets for the treatment of bacterial and viral infection, cancer, and autoimmune disease Carbohydrates act as antigens Carbohydrate ‘tag’ modified
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7. Agents acting on carbohydrates
Carbohydrate ‘tag’ Ceramide ‘anchor’ Top diagram refreshed
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7. Agents acting on carbohydrates
Antibodies Proteins produced by the immune system Recognise and bind to foreign antigens Y-shaped molecules consisting of 2 heavy and 2 light chains Variable region at tips of the arms Light chain Heavy chain
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7. Agents acting on carbohydrates
Antibodies Antibodies bind to foreign antigens on foreign cells Mark out the cell for destruction Immune system destroys the cell Antibodies have been designed as anticancer agents Invasion warning! Antibodies Antibody binding Cell destruction Foreign cell Antigen
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