Drug-Target Interaction Lecture Notes PDF

Drug-target interaction M. Sc. HAYA SALEH EL-QADERI College of Pharmacy Amman Arab university  Drug Targets Binding sites are typically hydrophobic hollows or clefts on the surface of macromolecules. Binding interactions typically involves inte...

Drug-target interaction M. Sc. HAYA SALEH EL-QADERI College of Pharmacy Amman Arab university  Drug Targets Binding sites are typically hydrophobic hollows or clefts on the surface of macromolecules. Binding interactions typically involves intermolecular bonds. Most 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 groups. Specific regions within the binding site that are involved in the binding interactions are called binding regions. Drug Targets  Drug Targets Binding 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 target Important to the pharmacological effect of the drug  Drug-Target interactions Drugs are chemically synthesized chemicals that control, prevent, cure and diagnose various diseases and illnesses. They do so by reacting with various macromolecules in the human body and elicit some form of positive biological response. Identifying the interactions between drugs and target proteins is a key step in drug discovery. Identifying the interactions helps to understand the disease mechanism and to identify unexpected therapeutic activity or adverse side effects of drugs.  Intermolecular bonding forces 1. Electrostatic or ionic bond 2. Hydrogen bonds 3. Van der Waals interactions 4. Dipole-Dipole interactions 5. Ion-dipole interactions 6. Induced dipole interactions  Intermolecular bonding forces 1. Electrostatic or ionic bond Strongest of the intermolecular bonds (20-40 kJ mol -1 ) Takes place between groups of opposite charge The strength of the ionic interaction is inversely proportional to the distance between the two charged groups The 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 site  Intermolecular bonding forces 2. Hydrogen bonds Vary in strength Weaker 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) The electron deficient hydrogen is usually attached to a heteroatom (O or N) The electron deficient hydrogen is called a hydrogen bond donor The electron rich heteroatom is called a hydrogen bond acceptor  Intermolecular bonding forces The 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 180o  Intermolecular bonding forces Examples of strong hydrogen bond acceptors – carboxylate ion, phosphate ion, tertiary amine Examples of moderate hydrogen bond acceptors – carboxylic acid, amide oxygen, ketone, ester, ether, alcohol Examples of poor hydrogen bond acceptors – sulfur, fluorine, chlorine, aromatic ring, amide nitrogen, aromatic Example of good hydrogen bond donors – Quaternary ammonium ion  Intermolecular bonding forces 3. Van der Waals interactions Very weak interactions (2-4 kJ mol -1 ) Occur between hydrophobic regions of the drug and the target Due to transient areas of high and low electron densities leading to temporary dipoles Interactions drop off rapidly with distance Drug must be close to the binding region for interactions to occur The overall contribution of van der Waals interactions can be crucial to binding  Intermolecular bonding forces 4. Dipole-dipole interactions Can occur if the drug and the binding site have dipole moments Dipoles align with each other as the drug enters the binding site Dipole alignment orientates the molecule in the binding site Orientation 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 regions The strength of the interaction decreases with distance more quickly than with electrostatic interactions, but less quickly than with van der Waals interactions Intermolecular bonding forces  Intermolecular bonding forces 5. Ion-dipole interactions Occur where the charge on one molecule interacts with the dipole moment of another Stronger than a dipole-dipole interaction Strength of interaction falls off less rapidly with distance than for a dipole-dipole interaction  Intermolecular bonding forces 6. Induced dipole interactions Occur where the charge on one molecule induces a dipole on another Occurs between a quaternary ammonium ion and an aromatic ring  Desolvation Penalties Polar regions of a drug and its target are solvated prior to interaction Desolvation is necessary and requires energy The energy gained by drug-target interactions must be greater than the energy required for desolvation  Hydrophobic Interactions Hydrophobic 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 entropy Interactions between the hydrophobic interactions of a drug and its target ‘free up’ the ordered water molecules Results in an increase in entropy Beneficial to binding energy Adrenaline THE END