Receptors 4

Drug-Receptor interactions

Lock and key model

the drug is complementary to the receptor

induced fit model

both the drug and the receptor both adjust their shapes to provide an optimal fit

conformational-selection model

protein receptor fluctuates between several conformational states. only some of these states allow binding to the drug/ligand

Drug targets include

proteins (receptors, enzymes, binding sites on ion channels)

nonproteins (DNA)

Pharmacophore

minimum chemical features necessary to elicit the biological response at a given biological target

Pharmacodynamics

the study of the effects of drugs on the body. this includes the interaction of drugs with their biological targets

covalent bonds

irreversible link to the receptor

50-150 kcal/mol

seldom formed in drug-receptor interaction (exceptions: drug + enzyme or drug + DNA)

Sarin

nerve gas - organophosphorus compound

covalently bonds to AchE on the Ser residue

Ionic bonding

results from the attraction of oppositely charged groups on the drug and receptor

5-10 kcal/mol

strongest of noncovalent interactions

Plerixafor

competitive antagonist of CXCR4 receptor on leukocytes

amine groups form ionic bonds with acidic amino acids

dipole

when a carbon is bound to an electronegative atom, there is an asymmetric distribution of electrons in the covalent bond. The electrons lie closer to the electronegative atom.

This gives the carbon a partial positive charge and the electronegative atom a partial negative charge

Ion-dipole or dipole-dipole interactions

attractive forces between permanent dipoles on polar groups within a drug molecule and receptor (or an ion and a dipole)

1-7 kcal/mol

proper alignment is required for these interactions to occur

Relative strength of electrostatic interactions

ionic bond > ion dipole > dipole dipole

Hydrogen bonding

a type of dipole-dipole interaction

formed between a proton of group X-H (X = electronegative) and another electronegative atom which contains an unshared pair of electrons

2-5 kcal/mol

H-bond acceptors

ketone

ester

ether

thioether

disubstituted amides

disubstituted carbamates

pyridines

fluorine

Hydrogen bond donors

pyrrole

protonated amine

Hydrogen bond donors + acceptors

alcohol or hydroxyl

phenol

amide

unionized primary or secondary amines

unionized carboxylic acid

carbamate

urea

thiol

Cation-pi interactions

interaction between a cation and the center face of an aromatic ring

2-4 kcal/mol

aromatic rings in Phe, Trp, Tyr may interact with a positively charged functional group on a drug

positively charged side chain of Arg or Lys may interact with an aromatic ring on a drug structure

salt bridge

noncovalent interaction between 2 ionized groups. mix of a hydrogen bond and an ionic interaction

pi-pi interactions

interaction between aryl rings

2 styles

• t-shaped edge to face

• parallel displaced stacking

hydrophobic interactions

describes the tendency of nonpolar compounds to transfer from water to an organic phase

attraction between nonpolar groups on a drug and lipophilic regions on a receptor

widespread because nearly all drugs have nonpolar parts

0.7 kcal/mol

Van der Waals Attractions

an attraction between nonpolar portions of 2 molecules due to a temporary dipole in a C - C covalent bond within one molecule, which induces an opposite dipole in the approaching molecule

0.5 kcal/mol

nonpolar surface area determines the force of the attraction

optimal drug-receptor interactions

3-5 points of contact

many weak interactions = strong collective interaction