Drug Targets - 1 - Flashcards in University Pharmacy

Describe features of cell structure (1)

Animal/plant cells are eukaryotic cells (DNA enclosed in nucleus). Bacterial cells are prokaryotic (DNA in cytoplasm). DNA in nucleus contains genetic blueprint for life. Cytoplasm (fluid contents of cell). Organelles (structures within cell)

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Describe features of cell structure (2)

Mitochondria are the source of energy production (ATP from Krebs cycle). Ribosomes are cell's factories for making new proteins

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Describe features of a cell membrane (1)

Phospholipid bilayer. Hydrophobic tails interact via van der Waals interactions (no contact with aqueous media). Polar head groups interaction with water at inner/outer surfaces of membrane

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Describe features of a cell membrane (2)

Hydrophobic barrier around cell (prevent passage of water/polar molecules). Proteins float in cell membrane (intrinsic/extrinsic/transmembrane). Ion channels/carrier proteins. Receptors for ligands. Most enzymes of intracellular

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How do small polar molecules enter cells?

Via water-filled porins

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How do lipophilic molecules enter cells?

Via diffusion through lipid bilayer

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What are the three main locations for drug targets?

Cell membrane, cytoplasm, nuclus

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Give examples of drug targets

Proteins (receptors in cell membrane/signal transductions, intracellular enzymes/biotransformation). Lipids (cell membrane lipids). Nucleic acids (DNA/older anti-cancer agents, RNA - ribosomes). Carbohydrates (cell surface, antigens/recognition)

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Describe features of drug targets (1)

Mostly proteins. Macromolecules (large). Drugs are usually smaller than their targets. Drugs interact with targets by binding to specific binding sites (hydrophobic pockets on surface of macromolecules, active site of enzymes/receptors)

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Describe features of drug targets (2)

Binding interactions involve non-covalent intermolecular bonds. Most drugs are in equilibrium between being bound and in solution. Binding regions (specific regions within binding site that are involved in binding interactions)

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State features of generic binding of a ligand to a protein

Ligand binds to protein to form a complex. Ligand is binding to a precise pocket in the protein and the ligand is much smaller than the protein

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Describe features of ionic bonding (1)

Electrostatic bonding. Strongest of intermolecular bonds (20-40 kJ/mol). Takes place between groups of opposite charge. Occur between protonated amine and deprotonated acid. At pH7 amines will be protonated (pKa 10) and acids deprotonated (pKa 4)

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Describe features of ionic bonding (2)

Strength of interaction drops less rapidly with distance than with other forms of intermolecular interactions. Ionic bonds are important initial interactions as drug approaches binding site. Could have - charged drug and + charged target (vice versa)

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Describe features of ionic bonding (3)

E.g. hydrochloride salt (rimantidine, racemic mixture). Side chain ionised and negatively charged. Protonated amine interacts with deprotonated acid

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Describe features of H bonds (1)

Vary in strength. Weaker than ionic bonds. H bond between electron deficient H and electron rich heteroatom (N or O). Electron deficient H attached to heteroatom (O or N). Electro deficient H (H bond donor), electron rich heteroatom (H bond acceptor)

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Describe features of H bonds (2)

Drug with HBD and target with HBA (and vice versa). Interaction involves orbital overlap (directional). Optimum orientation where X-H bond points directly to lone pair on Y (180 angle). H bond distance ~0.3 nM between heavy atoms

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Describe features of H bonds (3)

H bonding in DNA base pairing (e.g. adenine and thymine). H bonding networks can become quite complex

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Give examples of strong H bond acceptors (3)

Carboxylate ion, phosphate ion and tertiary amine

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Give examples of moderate H bond acceptors (6)

Carboxylic acid, amide oxygen, ketone, ester, ether, alcohol

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Give examples of poor H bond acceptors (6)

Sulfur, fluorine, chlorine, aromatic ring, amide nitrogen and aromatic amine

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Give examples of good H bond donors (2)

Quaternary ammonium ion, amide NH

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Describe features of non-specific hydrophobic interactions (1)

Easy to define ionic interactions/H bonds (e.g. X-ray structures). Hydrophobic interactions are weak/non-specific/SA dependent. Van der Waals theory (temporary dipoles formed in drug and target). Desolvation theory (increase d entropy drives binding)

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Describe features of non-specific hydrophobic interactions (2)

Hydrophobic/van der Waals interactions used interchangeably in med chem literature. Drug must be close to binding region for interactions to occur. Contribution of van der Waals/hydrophobic interactions can be crucial to drug binding

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Describe features of non-specific hydrophobic interactions (3)

Can be a bigger contribution to binding than ionic interactions. Simple ball and stick representation doesn't accurately describe the surface of a molecule (better represented by clouds of differing electron density)

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Describe features of dipole-dipole interactions (1)

Can occur if drug and binding site have dipole moments. Dipoles align with each other as drug enters binding site. Dipole alignment can orientate a drug in the binding site

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Describe features of dipole-dipole interactions (2)

Orientation is beneficial if other binding groups are positioned correctly wrt corresponding binding regions. Strength of interaction decreases with distance more quickly than ionic interactions but less quickly than van der Waals interactions

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Describe features of dipole-dipole interactions (3)

Very difficult to identify in a drug/protein X-ray without extensive computational work

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Describe features of ion-dipole interactions

Where charge on one molecule interacts with dipole moment of another molecule. Stronger than dipole-dipole interaction. Strength of interaction falls off less rapidly with distance than for a dipole-dipole interaction

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Describe features of induced dipole interactions

Occurs where charge on one molecule induces a dipole on another. Occurs between quaternary ammonium ion and an aromatic ring

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Describe features of desolvation penalties (1)

Polar regions of a drug and its target are solvated prior to interaction. Desolvation is necessary and requires energy. Energy gained by drug-target interactions must be greater than energy required for desolvation

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Describe features of desolvation penalties (2)

Desolvation penalties often invoked when a potential drug molecule doesn't bind as well as hoped

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Describe features of entropy penalties (1)

Binding affinity of a ligand is related to delta G of the binding event. Ionic interactions, hydrophobic interactions etc. only affect enthalpy (delta H). Loss of conformational freedom of a ligand decreases entropy (delta S).

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Describe features of entropy penalties (2)

Decrease in entropy is bad for binding. With the right conformational constraint very high binding can be achieved. Delta G = delta H - (T x delta S). The lower the IC50 the greater the activity. Constrained active conformation

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Describe features of entropy penalties (3)

Smaller loss of entropy on binding compared to the activity of other compounds

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Describe features of DNA as a possible target (1)

Modest success achieved with drugs that bind DNA. Quinacrine binds to DNA by intercalation. Effective against various solid tumours. This type of approach is hampered by toxicity issues. Greater selectivity can be achieved targeting proteins

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Describe features of DNA as a possible target (2)

Gepotidacin - binds DNA and protein, no toxicity issues

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Drug Targets - 1

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