Drug-Receptor Bonding

Ionic : the strongest type of non-covalent bond. This results from the attraction of ions with opposite charges.

R1

NR

H

R2

OR3

Ion-Dipole : results when there is an attraction between an ion and the partial charge of a dipole of the opposite polarity.

Dipole-Dipole : Here a partially positive atom in a dipole is attracted to a partially negative atom in another dipole.

Hydrogen Bonding: A dipole-dipole interaction where on of the constituents is a hydrogen attached to a heteroatom.

Hydrogen bonds

X HDrug

Y TargetDrug X

TargetHY++

- ---

HBD HBA HBA HBD

– 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 (HBD).

– The electron rich heteroatom is called a hydrogen bond acceptor (HBA).

Hydrogen bonds

YX H YX H

Hybridisedorbital

Hybridisedorbital

1sorbital

HBAHBD

– 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.

Hydrogen bonds

• 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 amine.

• Example of good hydrogen bond donors- Quaternary ammonium ion.

Lone pair electrons

Water can act as an H-bond Donor or Acceptor

Donates H

Accepts H

Examples ofH-bonding interactions

The Hydrophobic Effect : when two alkyl chains approach one another, water is extruded from the space in between them, resulting in an increase in entropy, and thus a decrease in energy.

Charge-Transfer Complexes : a lone pair of electrons is "shared" with a neighboring group that has considerable π character.

Van der Waals Forces : one carbon in a chain approaches another carbon on a neighboring chain, causing a perturbation known as an induced dipole. These opposite partial charges then attract one another.

Drugs may also bind to receptors using covalent bonding. This may be a permanent bond, in which case the receptor or enzyme target is "killed", or it may be transient.

Drug Interaction with Receptor

– NT binds to receptorNT = keyReceptor = lock

Lock & Key Model

Receptor A

NT

Receptor A

NT

Receptor BReceptor A

NT

NT

Receptor BReceptor A

NT Drug A

Drug B

HO

HO CH

OH

CH2 NHCH3

ADRENALINE =

HO

CH

OH

CH2 NHCH3

PHENYLEPHRINE =

*

Activates and adrenoceptors

Activates adrenoceptors

HO

HO CH

OH

CH2 NHCH(CH3)2

ISOPRENALINE = Activates receptors

*

a-Adrenoceptor

H-Bondingregion

H-Bondingregion

H-Bondingregion

Van der Waalsbonding region

Ionicbondingregion

ADRENALINE

a-Adrenoceptor

b-Adrenoceptor

ADRENALINE

SALBUTAMOL

b-Adrenoceptor

a-Adrenoceptor

SALBUTAMOL

SALBUTAMOL

a-Adrenoceptor

Dose = amount of drug administered to the patient

Response = effect in the body produced by the drug

Drug + Receptor Drug-Receptor Complex

Response

Dose Response Relationships

Response

Log Drug Concentration [Molar]

0

100

50

ED50

KEY PARAMETERS

1. Dose required to produce any effect at all.2. ED50 = effective dose to produce 50% response3. Dose required to produce maximum effect4. Dose that produces a toxic response.

34

1

2

Efficacy (or Intrinsic Activity) – ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but NOT efficacy

Log Drug Concentration [Molar]

0

100

50

ED501

2

Potency vs Efficacy• Potency – how much drug is required to produce a

certain effect.

Response

Analgesia

Dose

hydromorphone

morphine

codeine

aspirin

Relative Potency

Log Drug Concentration [Molar]

0

100

50

ED50

1

2

Potency vs Efficacy

• Efficacy – how large an effect the drug produces.

Response

Agonists Drugs

Drugs that interact with and activate receptors, they possess both affinity and efficacy.

• Agonist binds reversibly to the binding site • Similar intermolecular bonds formed as to natural

messenger• Induced fit alters the shape of the receptor in the same

way as the normal messenger• Receptor is activated• Agonists are often similar in structure to the natural

messenger

E

Agonist

R E

Agonist

R

Signal transduction

Agonist

R

Induced fit

Antagonists Drugs• Drugs that interact with receptors but do not change them.

• They have affinity but no efficacy.

• Two types:

• Competitive (reversible) antagonists.

• Non competitive (irreversible) antagonists.

• Competitive (reversible) antagonists

• Antagonist binds reversibly to the binding site • Intermolecular bonds involved in binding.• Different induced fit means receptor is not activated• No reaction takes place on antagonist.• Level of antagonism depends on strength of

antagonist binding and concentration.• Messenger is blocked from the binding site.• Increasing the messenger concentration reverses

antagonism.

An

ER

M

An

R

Non competitive (irreversible) antagonists

• Antagonist binds irreversibly to the binding site.• Different induced fit means that the receptor is not

activated.• Covalent bond is formed between the drug and the

receptor• Messenger is blocked from the binding site.• Increasing messenger concentration does not reverse

antagonism.

X

OH OH

X

O

Covalent Bond

Irreversible antagonism

Non competitive (reversible) allosteric antagonists

• Antagonist binds reversibly to an allosteric site.• Intermolecular bonds formed between antagonist and

binding site.• Induced fit alters the shape of the receptor.• Binding site is distorted and is not recognised by the

messenger.• Increasing messenger concentration does not reverse

antagonism.

ACTIVE SITE (open)

ENZYMEReceptor

Allostericsite

Binding site

(open)ENZYMEReceptor

Inducedfit

Binding siteunrecognisable

Antagonist

Effectiveness, toxicity, lethality

• ED50 - Median Effective Dose 50; the dose at which 50 percent of the population or sample manifests a given effect; used with quantal dr curves

• TD50 - Median Toxic Dose 50 - dose at which 50 percent of the population manifests a given toxic effect

• LD50 - Median Toxic Dose 50 - dose which kills 50 percent of the subjects

Quantification of drug safety

Therapeutic Index = TD50 or LD50

ED50

dose

Drug A

sleepdeath

100

50

0ED50 LD50

PercentResponding

dose

Drug B

sleepdeath

100

50

0ED50 LD50

PercentResponding

Stereochemical Aspects in Drug Receptor Interaction

– Drug molecules must generally interact with biomolecules in a very specific way to elicit a pharmacological response.

– Biomolecules are chiral, they often discriminate between isomers of a given drug molecule.

– The stereochemistry of a drug can impact its ability to bind to its target.

The reason for chiral recognition by drug receptors is a three-point interaction of the agonist or substrate with the receptor or enzyme active site, respectively.

Examples: Only the (-) enantiomer of epinephrine has the OH group in the binding site, and therefore has a much more potent pressor activity.

▪ Enantiomers interact with living systems in very different ways and results for example in:

− Different smell

Olfactory sensors are chiral

(R)

CH3

O

H

(S)

CH3

HH2C

CH3

CH2

H3C

O

Mirror plane

(R) Spearmint oil (S) caraway oil

− Different taste

H3NN

OCH3

O

H O

H

H

O

O

H3NN

OCH3

O

H O

H

H

O

O

Aspartame

(S,S) (R,R)

Bitter!!160 Times Sweeter than Sugar

Taste buds are chiral

− Different drug effects• Biomolecules, thus, can discriminate between enantiomers (isomers) of a given drug molecule.

• The net result is same or different pharmacologic/ pharmacokinetic/ toxicologic activities

Biological Discrimination

=>

THALIDOMIDE: DISASTROUS BIOLOGICAL ACTIVITY OF THE “WRONG” ENANTIOMER

N

N

O

O

O

O

H

H

* N

N

O

O

O

O

H

H

*

(R)-isomer (S)-isomer

− In the 1960’s thalidomide was given as racemic mixture (RS) to pregnant women to reduce the effects of morning sickness (Nausea and vomiting of pregnancy).

− This led to many disabilities in babies and early deaths in many cases.

The photographs are both from ‘Molecule of the Month’ at Bristol University: http://www.chm.bris.ac.uk/motm/thalidomide/start.html

− Later found that only the R-isomer can be used safely

− In 1998 thalidomide has been approved by FDA to reduce the immune system’s inflammatory response in a host of illnesses, including arthritis, lupus, cancer, leprosy, and AIDs.

CF3

O NHCH3

HCF3

OCH3NH

H

(S)-Fluoxetine (R)-Fluoxetine

Copyright© 1999, Michael J. Wovkulich. All rights reserved.

− The pure S enantiomer prevents migraines.

− A racemic mixture of fluoxetine (sold as the antidepressant Prozac) doesn’t prevent migraines.

OH

OH

C(S)

HOOC

HH2N

HO

HO

C(S)

COOH

H NH2

L-DopaAnti-Parkinson’s disease drug

D-DopaBiologically inactivehas serious side effects

Likewise, cis/trans isomers of cyclic compounds, or Z/E isomers of alkenes are also expected to have different binding potency and therefore also different biological activity.

OH

HO

OH

HO HO

OH

OH

HO

OH

HO

Estradiol E-DES(Active)

Z-DES(Inactive)

Estradiol & E-DES overlay

According to this theory, the "right" isomer is called the eutomer.

The "wrong" isomer is called the distomer.

The ratio of the activities of the eutomer and the distomer is called the eudismic ratio, and converting the equation to log form affords the eudismic index, EI.

Acetylcholine may interact with the muscarinic receptor of postganglionic parasympathetic nerves and with Acetylcholine esterases in the fully extended confirmation and in a different more-folded structure with the nicotinic receptors at ganglia and at neuromuscular junctions.

– Gauche conformer = muscarinic                 – Anti conformer = nicotinic

Conformation is a spatial arrangement of a molecule of a given constitution and configuration.

• Proteins are built from L-amino acids, which implies that enzymes - the catalysts of nature - are chiral

• Consequently, most biomolecules are chiral (sugars, DNA, proteins, amino acids, steroids)

• Also, receptors (drug, taste, biopharmaceuticals, agrochemicals) are chiral and the natural ligand to a receptor is often only one specific enantiomer

• This is why mirror image molecules can have radically different activities (effectivity, toxicity, taste) in the body.

COOH COOH

R R

NH2 NH2

H H

C C

Life is Chiral

– Enantiomers: Optical isomers which are mirror images

– Diastereoisomers: Optical isomers which are not mirror images

– Racemates: Mixture of equal parts of enantiomers

CH

OH

HC

NH

CH3

CH3

Ph

HC OH

HC

CH3

NHCH3

Ph

CHHO

CH

CH3

H3CHN

Ph

CH

HC

CH3

NHCH3

HO

Ph

HC

CH

CH3

H3CHN

OH

Ephedrine

D(-) Ephedrine L(+) Ephedrine

D(-) Pseudoephedrine L(+) Pseudoephedrine

(mp = 40oC, []D = -6o)

(mp = 76oC, []D = -50o)

Isomer Relative Activity

D (-) PseudoephedrineDL PseudoephedrineL (+) PseudoephedrineL (+) EphedrineDL EphedrineD (-) Ephedrine

147

112636

Pressor activities of ephedrines

C

H2C

N+

H3C

H

H

H

OH

OH

OH

XAnionicsite

FlatArea

Receptor

(-)-Epinephrine - more active- Ephedrine (more active)

Stereochemistry