1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter Two THE WHY & THE WHEREFORE: DRUG TARGETS Jony Mallik M.Pharm

1 © Contents 1.Cell Structure (2 slides) 2.Cell Membrane (4 slides) 3.Drug Targets (4 slides) 4.Intermolecular Bonding Forces 4.1.Electrostatic or ionic bond 4.2.Hydrogen bonds (3 slides) 4.3.Van der Waals interactions 4.4.Dipole-dipole/Ion-dipole/Induced dipole interactions (4 slides) 5.Desolvation penalties 6.Hydrophobic interactions 7.Drug Targets - Cell Membrane Lipids (2 slides) 8.Drug Targets – Carbohydrates (2 slides) [26 slides]

1 © 1. Cell Structure Human, animal and plant cells are eukaryotic cellsHuman, animal and plant cells are eukaryotic cells The nucleus contains the genetic blueprint for life (DNA)The nucleus contains the genetic blueprint for life (DNA) The fluid contents of the cell are known as the cytoplasmThe fluid contents of the cell are known as the cytoplasm Structures within the cell are known as organellesStructures within the cell are known as organelles Mitochondria are the source of energy productionMitochondria are the source of energy production Ribosomes are the cell’s protein ‘factories’Ribosomes are the cell’s protein ‘factories’ Rough endoplasmic reticulum is the location for protein synthesisRough endoplasmic reticulum is the location for protein synthesis

1 © Phospholipid Bilayer Exterior High [Na + ] Interior High [K + ] 2. Cell Membrane Proteins

1 © 2. Cell Membrane Polar Head Group Hydrophobic Tails CHCH 2 CH 2 OO O POO O CH 2 CH 2 NMe 3 OO

1 © 2. Cell Membrane

1 © The cell membrane is made up of a phospholipid bilayerThe cell membrane is made up of a phospholipid bilayer The hydrophobic tails interact with each other by van der Waals interactions and are hidden from the aqueous mediaThe hydrophobic tails interact with each other by van der Waals interactions and are hidden from the aqueous media The polar head groups interact with water at the inner and outer surfaces of the membraneThe polar head groups interact with water at the inner and outer surfaces of the membrane The cell membrane provides a hydrophobic barrier around the cell, preventing the passage of water and polar moleculesThe cell membrane provides a hydrophobic barrier around the cell, preventing the passage of water and polar molecules Proteins are present, floating in the cell membraneProteins are present, floating in the cell membrane Some act as ion channels and carrier proteinsSome act as ion channels and carrier proteins

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1 © Proteins Receptors Enzymes Carrier proteins Structural proteins (tubulin) Lipids Cell membrane lipids Nucleic acids DNA RNA Carbohydrates Cell surface carbohydrates Antigens and recognition molecules 3. Drug targets

1 © Drug targets are large molecules - macromoleculesDrug targets are large molecules - macromolecules Drugs are generally much smaller than their targetsDrugs are generally much smaller than their targets Drugs interact with their targets by binding to binding sitesDrugs interact with their targets by binding to binding sites Binding sites are typically hydrophobic pockets on the surface of macromoleculesBinding sites are typically hydrophobic pockets on the surface of macromolecules Binding interactions typically involve intermolecular bondsBinding interactions typically involve intermolecular bonds Most drugs are in equilibrium between being bound and unbound to their targetMost drugs are in equilibrium between being bound and unbound to their target Functional groups on the drug are involved in binding interactions and are called binding groupsFunctional groups on the drug are involved in binding interactions and are called binding groups Specific regions within the binding site that are involved in binding interactions are called binding regionsSpecific regions within the binding site that are involved in binding interactions are called binding regions

1 © Macromolecular target Drug Unbound drug Macromolecular target Drug Bound drug Binding site Drug Binding site Binding regions Binding groups Intermolecular bonds 3. Drug targets

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1 © Binding interactions usually result in an induced fit where the binding site changes shape to accommodate the drugBinding interactions usually result in an induced fit where the binding site changes shape to accommodate the drug The induced fit may also alter the overall shape of the drug targetThe induced fit may also alter the overall shape of the drug target Important to the pharmacological effect of the drugImportant to the pharmacological effect of the drug Induded Fit and Hexokinase LINKInduded Fit and Hexokinase LINKInduded Fit and Hexokinase LINKInduded Fit and Hexokinase LINK

1 © 4. Intermolecular bonding forces 4.1 Electrostatic or ionic bond Strongest of the intermolecular bonds (20-40 kJ mol -1 )Strongest of the intermolecular bonds (20-40 kJ mol -1 ) Takes place between groups of opposite chargeTakes place between groups of opposite charge The strength of the ionic interaction is inversely proportional to the distance between the two charged groupsThe strength of the ionic interaction is inversely proportional to the distance between the two charged groups Stronger interactions occur in hydrophobic environmentsStronger interactions occur in hydrophobic environments The strength of interaction drops off less rapidly with distance than with other forms of intermolecular interactionsThe strength of interaction drops off less rapidly with distance than with other forms of intermolecular interactions Ionic bonds are the most important initial interactions as a drug enters the binding siteIonic bonds are the most important initial interactions as a drug enters the binding site

1 © Rimantidine (racemic mixture) Formulated as Hydrochloride Salt D44 = Aspartic Acid = Asp44 Side chain is ionized and negatively charged

1 © 4. Intermolecular bonding forces 4.2 Hydrogen bonds Vary in strengthVary in strength Weaker than electrostatic interactions but stronger than van der Waals interactionsWeaker than electrostatic interactions but stronger than van der Waals interactions A hydrogen bond takes place between an electron deficient hydrogen and an electron rich heteroatom (N or O)A hydrogen bond takes place between an electron deficient hydrogen and an electron rich heteroatom (N or O) The electron deficient hydrogen is usually attached to a heteroatom (O or N)The electron deficient hydrogen is usually attached to a heteroatom (O or N) The electron deficient hydrogen is called a hydrogen bond donorThe electron deficient hydrogen is called a hydrogen bond donor The electron rich heteroatom is called a hydrogen bond acceptorThe electron rich heteroatom is called a hydrogen bond acceptor

1 © 4. Intermolecular bonding forces 4.2 Hydrogen bonds HBAHBD The interaction involves orbitals and is directionalThe interaction involves orbitals and is directional Optimum orientation is where the X-H bond points directly to the lone pair on Y such that the angle between X, H and Y is 180 oOptimum orientation is where the X-H bond points directly to the lone pair on Y such that the angle between X, H and Y is 180 o

1 © 4. Intermolecular bonding forces 4.2 Hydrogen bonds Examples of strong hydrogen bond acceptorsExamples of strong hydrogen bond acceptors - carboxylate ion, phosphate ion, tertiary amine Examples of moderate hydrogen bond acceptorsExamples of moderate hydrogen bond acceptors - carboxylic acid, amide oxygen, ketone, ester, ether, alcohol Examples of poor hydrogen bond acceptorsExamples of poor hydrogen bond acceptors - sulfur, fluorine, chlorine, aromatic ring, amide nitrogen, aromatic amine Example of good hydrogen bond donorsExample of good hydrogen bond donors - Quaternary ammonium ion

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1 © Sometimes the Hydrogen-bonding networks Can become quite complex

1 © 4. Intermolecular bonding forces 4.3 Van der Waals interactions Binding site DRUG -- ++ Very weak interactions (2-4 kJmol -1 )Very weak interactions (2-4 kJmol -1 ) Occur between hydrophobic regions of the drug and the targetOccur between hydrophobic regions of the drug and the target Due to transient areas of high and low electron densities leading to temporary dipolesDue to transient areas of high and low electron densities leading to temporary dipoles Interactions drop off rapidly with distanceInteractions drop off rapidly with distance Drug must be close to the binding region for interactions to occurDrug must be close to the binding region for interactions to occur The overall contribution of van der Waals interactions can be crucial to bindingThe overall contribution of van der Waals interactions can be crucial to binding ++ -- Hydrophobic regions Transient dipole on drug ++ -- van der Waals interaction

1 © A van der Waals Surface around a small molecule, Showing potential for van der waals interactions

1 © 4. Intermolecular bonding forces 4.4 Dipole-dipole interactions Can occur if the drug and the binding site have dipole momentsCan occur if the drug and the binding site have dipole moments Dipoles align with each other as the drug enters the binding siteDipoles align with each other as the drug enters the binding site Dipole alignment orientates the molecule in the binding siteDipole alignment orientates the molecule in the binding site Orientation is beneficial if other binding groups are positioned correctly with respect to the corresponding binding regionsOrientation is beneficial if other binding groups are positioned correctly with respect to the corresponding binding regions Orientation is detrimental if the binding groups are not positioned correctly with respect to corresponding binding regionsOrientation is detrimental if the binding groups are not positioned correctly with respect to corresponding binding regions The strength of the interaction decreases with distance more quickly than with electrostatic interactions, but less quickly than with van der Waals interactionsThe strength of the interaction decreases with distance more quickly than with electrostatic interactions, but less quickly than with van der Waals interactions

1 © Binding site Localised dipole moment Dipole moment R C R O   Binding site R C R O 4.4 Dipole-dipole interactions 4. Intermolecular bonding forces

1 © 4.4 Ion-dipole interactions Occur where the charge on one molecule interacts with the dipole moment of anotherOccur where the charge on one molecule interacts with the dipole moment of another Stronger than a dipole-dipole interactionStronger than a dipole-dipole interaction Strength of interaction falls off less rapidly with distance than for a dipole-dipole interactionStrength of interaction falls off less rapidly with distance than for a dipole-dipole interaction Binding site   R C R O   R C R O

1 © 4. Intermolecular bonding forces 4.4 Induced dipole interactions Occur where the charge on one molecule induces a dipole on anotherOccur where the charge on one molecule induces a dipole on another Occurs between a quaternary ammonium ion and an aromatic ringOccurs between a quaternary ammonium ion and an aromatic ring Binding site RNR 3 

1 © R C R O O H H HH O H H O H H O O H Desolvation - Energy penaltyBinding - Energy gain O H R C R O Binding site R C R O O H 5. Desolvation penalties Polar regions of a drug and its target are solvated prior to interactionPolar regions of a drug and its target are solvated prior to interaction Desolvation is necessary and requires energyDesolvation is necessary and requires energy The energy gained by drug-target interactions must be greater than the energy required for desolvationThe energy gained by drug-target interactions must be greater than the energy required for desolvation

1 © Unstructured water Increase in entropy Drug DRUG Structured water layer round hydrophobic regions Hydrophobic regions regions Water Binding site Drug DRUG Binding 6. Hydrophobic interactions Hydrophobic regions of a drug and its target are not solvatedHydrophobic regions of a drug and its target are not solvated Water molecules interact with each other and form an ordered layer next to hydrophobic regions - negative entropyWater molecules interact with each other and form an ordered layer next to hydrophobic regions - negative entropy Interactions between the hydrophobic interactions of a drug and its target ‘free up’ the ordered water moleculesInteractions between the hydrophobic interactions of a drug and its target ‘free up’ the ordered water molecules Results in an increase in entropyResults in an increase in entropy Beneficial to binding energyBeneficial to binding energy

1 © Hydrophobic region Drugs acting on cell membrane lipids - Anaesthetics and some antibiotics Action of amphotericin B (antifungal agent) - builds tunnels through membrane and drains cell - builds tunnels through membrane and drains cell 7. Drug Targets - Cell Membrane Lipids HydrophilicHydrophilicHydrophilic

1 © Polar tunnel formed Escape route for ions 7. Drug Targets - Cell Membrane Lipids

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1 © Fungal Drug Targets

1 © 8. Drug Targets - Carbohydrates Carbohydrates play important roles in cell recognition, regulation and growthCarbohydrates play important roles in cell recognition, regulation and growth Potential targets for the treatment of bacterial and viral infection, cancer and autoimmune diseasePotential targets for the treatment of bacterial and viral infection, cancer and autoimmune disease Carbohydrates act as antigensCarbohydrates act as antigens Cellmembrane

1 © 7. Drug Targets - Carbohydrates

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1 © Assigned Reading An Introduction to Medicinal Chemistry by Graham Patrick, pp Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12 th edition, Chapter 3, Pharmacodynamics: Molecular Mechanisms of Drug Action, pp Caceres, Rafael Andrade; Pauli, Ivani; Timmers, Luis Fernando Saraiva Macedo; Filgueira de Azevedo, Walter, Jr. Molecular recognition models: a challenge to overcome. Current Drug Targets (2008), 9(12), LinkLink Hof, Fraser; Diederich, Francois. Medicinal chemistry in academia: molecular recognition with biological receptors. Chemical Communications (Cambridge, United Kingdom) (2004), (5), LinkLink

1 © Optional Reading Edelman, Gerald M. Biochemistry and the Sciences of Recognition. Journal of Biological Chemistry (2004), 279(9), LinkLink Babine, Robert E.; Bender, Steven L. Molecular Recognition of Protein-Ligand Complexes: Applications to Drug Design. Chemical Reviews (Washington, D. C.) (1997), 97(5), LinkLink