1. Drug-Receptor Interactions What is a receptor?  Observed physiological response of drugs often result from the drug’s interaction with a macromolecular entity on or within a cell. The macromolecular entity with which the drug interacts is referred to as a RECEPTOR.

2. A Tubulin Dimer with the Drug, Taxol bound to it’s Receptor

3. Types of receptors  Usually proteins, which mediate effects of  neurotransmitters such as dopamine, norepinephrine, Ach, etc.  autacoids such as histamine, prostaglandins, 5-HT, etc.  hormones such as estrogen, testosterone, cortisol etc.  Enzymes: may be inhibited or even activated by drugs e.g. Acetyl Cholinesterase (receptor) responsible for Ach hydrolysis  Transport Proteins: e.g. Na/K ATPase, receptor for digitalis glycosides {digoxin (Lanoxin, Lanoxicaps), digitoxin (Crystodigin)}  Structural Proteins: Tubulin (Proteins that make up microtubules) is a receptor for certain anticancer drugs  Nucleic Acids: A number of anticancer drugs intercalate into DNA which results in distortion of double helices and compromising replication and transcription of genes.

4. Complementarity in Topology (Shapes, Sizes) (Substrate)

5. Complementarity in Polarity and Charges Examples DrugReceptor R-NH 3 + R-COO - ++

6. Binding Forces Between Drugs and Receptors  Drug Receptor Complex Formation is promoted by chemical bonds between functional groups on the drug and the receptor.  The strength of receptor binding depends on the type of bonds formed between the functional gps expressed in terms of energy.  Types of Bonds : 1. Van der Waals Forces 2. Dipole-Dipole and Dipole-Ion interactions 3. Hydrogen Bonding 4. Ionic Bonding 5. Hydrophobic interactions 6. Covalent Bonding

7. Types of Bonding in Drug-Receptor Interactions  Van der Waals Interaction (Dispersion Forces or London Dispersion Forces)  These are very weak forces that occur between all atoms and molecules including the noble gases.  Occur as a result of temporary induced dipoles in atoms or molecules  An induced dipole can induce dipoles in other atoms or molecules leading to VDW attractive forces on the order of 2 kJ/mole or less.

8. Dipole-Dipole and Dipole-Ion Interactions  Formed between molecules with permanent dipoles or charges  Examples of these types of dipole-dipole interactions are shown below  Energies can reach between 100-150 kJ/mole

9. Hydrogen Bonding Interaction  Formed between lone pairs of electrons and partial +ve charges on hydrogen atoms found on heteroatoms  This is a type of dipole-dipole interaction as shown below  Both inter and intramolecular hydrogen bonding are possible  Eg. H-bonds hold together the base pairs in DNA molecules  Energies range between 7-40 kJ/mole

10. Ionic Bonding  Formed between ions of opposite charges  These are very powerful forces that can reach as much as 700 kJ/mole.  An example of such bonding is shown below

11. Hydrophobic Interactions  These are indirect forces of attraction that arise as a result of an increase in entropy.  If a molecule of hydrocarbon (HC) is dropped in water, the disordered H 2 O molecules will rearrange themselves around the HC molecule since they could not form H-bonds with H 2 O.  Introduction of a 2nd HC molecule into the H 2 O will do likewise and in essence causing the ordering of the H 2 O molecules.  When the HC molecules are exposed to each other, they will squeeze the H 2 O molecules out and increase the disordered nature of the H 2 O molecules and hence increase in entropy.  The free energy of the resulting system is decreased by ~ 3.4 kJ/mole per CH 2 group. This thus favors association of the HC molecules and is called Hydrophobic Bonding

12. Covalent Bonding  Covalent bonds are formed by the sharing of electron pairs between atoms.  They are not important in drug receptor interactions. They do however occur occasionally. Eg. the drug phenoxybenzamine, an  - adrenergic blocker acts by forming a covalent bond with the receptor  Energies vary, but a single carbon-carbon bond is estimated to ~350kJ/mole C-CC=C

13. How Do Drug-Receptor Interactions lead to Physiological Responses?