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.

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

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.

Complementarity in Topology (Shapes, Sizes)

• (Substrate)

Complementarity in Polarity and Charges

Examples Drug Receptor

R-NH3+ R-COO-

CO H-O-R

d+

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 Forces2. Dipole-Dipole and Dipole-Ion interactions3. Hydrogen Bonding4. Ionic Bonding5. Hydrophobic interactions6. Covalent Bonding

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.Electrons

Nucleus

+

Symmetrical Electron Distribution

Unsymmetrical Electron Distribution

Weak VDW Forces between Atom

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

N R

R:H

O

Interaction between permanent Dipoles

N R

R:HO-

O

Interaction between a permanent

Dipole and an anion

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

O H N R

R:

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

NR

R

HO

O R

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 H2O molecules will rearrange themselves around the HC molecule since they could not form H-bonds with H2O.

Introduction of a 2nd HC molecule into the H2O will do likewise and in essence causing the ordering of the H2O molecules.

When the HC molecules are exposed to each other, they will squeeze the H2O molecules out and increase the disordered nature of the H2O molecules and hence increase in entropy.

The free energy of the resulting system is decreased by ~ 3.4 kJ/mole per CH2 group. This thus favors association of the HC molecules and is called Hydrophobic Bonding

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 a-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-C C=C

How Do Drug-Receptor Interactions lead to Physiological Responses?