Drug Molecular Properties and Structures

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Those slides adapted from:

• Dr Afaf Mohammed Lecture notes (University of Nizwa)

• www. Philadephia.edu.jo

• Beale and Block. Wilson and Gisvold’s textbook of Organic and Pharmaceutical chemistry. 2011

• Lemke et al. Foy’s principals of medicinal chemistry. 2008

• Patrick G L. An introduction to medicinal chemistry. 2013

Overview • Medicinal chemistry is an applied science that is focused on the design or

the discovery of new chemical entities (NCEs) and their development as useful drug molecules for the treatment of disease processes.

• A molecule is the smallest particle of a substance that retains the chemical identity of that substance, it is hold by two or more atoms held together by chemical bonds.

• Functional group is a cluster of atoms that determine the chemical and physical properties.

• Drug molecule possesses one or more functional groups positioned in a three dimensional space on a structural framework that enables the molecule to bind to a specific target.

• Drug-like molecule possesses chemical and physical properties that enable it to be a drug molecule.

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Overview • Pharmacophore is the three-dimentional arrangement of atoms within

a molecule that enable the bioactive face to interact with the desired receptor. So it is the active groups or atoms in a molecule that enable the biological activity.

• Molecular baggage is the other portions of the drug that is not part of the pharmacophore. It is responsible for holding the functional group atoms of the pharmacophore in a fixed geometric arrangement.

• Toxiphore is the three-dimentional arrangement of atoms in a drug molecule that is responsible for toxicity producing interactions. If the toxiphore does not overlap with the pharmacophore, then it is possible to redesign the molecule again to eliminate toxic portion.

• Metabophore is the three-dimentional arrangement of atoms in a dug molecule that are responsible for the metabolic properties.

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Physicochemical properties of a drug

A drug molecule is a compound that has the ability to bind specifically to a receptor

It should also be absorbed, distributed, metabolized and excreted by the body

This depends on the physicochemical properties of a drug including

1. Acid-base property

2. Water-lipid solubility

3. Size

4. Steric effect

5. Conformational isomerism

6. Stereoisomers: Optical isomerism and Geometric isomerism

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A drug is a chemical molecule, after introduction into the

body, a drug must pass through many barriers, survive

alternate site of attachment, storage, and avoid significant

metabolic destruction before it reaches the site of action

(receptor, cell, and or an enzyme).

Drug receptor complex

(R2x-1)

Drug + receptor

Pharmacological action

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The ideal drug molecule will show favorable binding

characteristics to the receptor such that the equilibrium

lies to the right, at the same time the drug will be

expected to dissociate from receptor and re-enter the

systematic circulation to be excreted.

Major exception is alkylating agent used and some

enzyme inhibitors both of these forms a covalent bond

with the cell or the receptor so either the cell will

destroy the receptor or replaced by new cell.

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Oral administration:

The drug that is administrated orally must go into solution in order

to pass through the gastrointestinal mucosa. The ability of the drug

to dissolve is governed by several factors including

•Structure

• Particle surface area

•Nature of the crystals

•Types of tablets coating

•Tablet matrix.

By varying the dosage form and the physical properties of the drug it

is possible to have a drug that dissolve quickly or slowly.

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Chemical modification is also used to a limited extent to

facilitate a drug reaching its desired target e.g.:

Olsalazine used in ulcerative colitis in a dimeric of the

pharmacological active mesalamine (5-amino salicylic acid).

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Parenteral administration:

Some patients cannot tolerate the drug orally or the

drug is rapidly metabolized to inactive product in the

liver before reaching the circulation as lidocaine, is

ineffective orally because it is removed by the first pass

metabolism.

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Protein buildings:

Drug + albumin Drug albumin complex (Rx 2-2)

The protein binding can

affect the

Drug's solubility

Biodistribution

Half-life

Interaction with

other drug.

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Tissue depots:

About 20-50% of the body weight is natural fat.

The more lipophilic the drug, the more likely it

will concentrate in these pharmacologically inert

depots. 13

• ACIDS ARE PROTON DONORS

acid is a substance that can dissociate to give H+ and a negative

ion (anion) which is called a conjugate base:

Ionisation and dissociation

• BASES ARE PROTON ACCEPTORS

Bases can accept a proton to form the positively charged cation ( conjugate acid of the base):

Ionisation and dissociation

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Common acidic functional groups

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Common basic functional groups

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Common neutral functional groups

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Ka =+

[HA]

pKa = - logKa = - log[H3O] - log

[H3O] [A-]

[A-]

[HA]

pKa = pH - log

log = pH - pKa

+

[A-]

[HA]

[A-]

[HA]

For Acidic Drugs

Henderson-Hasselbalch equation

10pH-pKa[A-]

[HA]=

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Here you need to consider that this equation can be consider for acids forms as (HA) and (BH+) acids

% of the ionized drug is given as

=[A-]

[HA] + [A-]

[A-]/[HA]

HA/HA + A-/HA

x 100

x 100

x 100

10pH-pKa

1 + 10pH-pKa=

= But 10pH-pKa[A-]

[HA]=

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• To predict the % of ionization of a functional group

• Only the unionised form of a drug can partition across biological membranes (providing the unionized form is lipophilic)

• The ionised form tends to be more water soluble [required for drug administration and distribution in plasma]

What is the importance of studying the pKa

values for Acidic and basic drugs?

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HA +H2O A- + H3O+

Lipid barrier

HA + H2O A- + H3O+

Lipid barrier

BH+ +H2O B + H3O+

BH+ +H2O B + H3O+

For Acidic drug

For Basic drug

pKa= 4.4

pKa= 7.8

NH

NH

O

O O

HC2H5

NH

NH

O

O O

C2H5

C2H5

It is a weak hypnotic

because at

physiological pH=

7.4 most of it will be

in the ionized form.

About 70% of which will

be in the unionized form

which readily pass the

lipid barrier.

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Weak acids

pH = pKa compound ~ 50% ionised

pH = pKa + 1 compound ~ 90% ionised

pH = pKa + 2 compound ~ 99% ionised

pH = pKa + 3 compound ~ 99.9% ionised

pH = pKa + 4 compound ~ 99.99% ionised

• pKa of aspirin is 3.5

• Physiological pH = 7.4 •pH = pKa+ 4

%ionisation= 99.99%

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Weak bases

pH = pKa compound ~50%ionised

pH = pKa - 1 compound ~ 90% ionised

pH = pKa - 2 compound ~ 99% ionised

pH = pKa - 3 compound ~ 99.9% ionised

pH = pKa - 4 compound ~ 99.99% ionised

phenypropanolamine

NH2

CH3

OH

NH3

CH3

OH

H • pH = pKa- 2

• pKa of phenylpropanolamine is 9.4

• Physiological pH = 7.4

%ionisation= 99% ionised 25

For acids: 1. a high pka means the species is predominantly

unionised, is a bad proton donor, and a weak acid

2. a low pka means the species is predominantly

ionised, is a good proton donor, and a strong acid

pH < pKa by 2 units, 99% unionised

pH > pKa by 2 units, 99% ionised

For bases: 1. a high pka means the species is predominantly ionised, is a

good proton acceptor, and a strong base

2. a low pka means the species is predominantly

unionised, is a bad proton acceptor, and a weak base

pH < pKa by 2 units, 99% ionised

pH > pKa by 2 units, 99% unionised

Remember the followings

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Acid-base properties of drugs

• The pKa and pKb of a drug do not tell if the drug will behave as an acid or a base in a solution.

e.g amines (pKa ~ 9) are basic

while phenols (pKa ~ 10) are acidic

• For a drug molecule to be an acid or a base depends on the nature of its functional groups.

• A drug molecule with a functional group that can donate hydrogen ion (H+) will be an acid

• A drug molecule with a functional group that can accept hydrogen ion (H+) will be a base

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• For molecules that contain multiple functional groups both acidic and basic groups, their ionization will depend on the solution (media)

• Example is Ciprofloxacin that contain acidic and basic functional group

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Ionisation and dissociation

Lemke et al. Foyes principals of medicinal chemistry. 2008. p. 30, 31

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Amoxicillin contain many function groups. At physiological pH:

The carboxylic acid will be in the ionized form carboxylate (pKa ˂ pH)

The primary amine will be 50 % protonated and 50 % in the free base (pKa = pH)

The phenol group will be in the unionized form (pKa ˃ pH)

Practice question

• Loratadine is an orally available drug, it has a pKa of 5, answer the followings according to its structure:

• Is it basic, acidic or neutral compound?

• Calculate the % ionization: • In stomach (pH = 2):

• In intestine (pH = 8):

• Based on your calculation, from where do you think loratadine will be absorbed?

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= 10-3

% ionization = 99.9% (under stomach pH)

tedUndissocia

dDissociatepKpH a 10log

tedUndissocia

dDissociate Ionized

Unionized

Ionized

Unionized

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Under intestinal pH:

= 103

% ionization = 0.1%

So loratadine will be mainly in unionized form

It will be better absorbed from intestinal membrane not from stomach

Ionized

Unionized

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Homework • Calculate the % of ionization of for ephedrine and indomethacin at pH

of stomach (pH=3.5), intestine (pH=8.0) and blood (pH=7.4).

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NH

OH

Ephedrine

O OH

O

O Cl

Indomethacin

2. Water-Lipid solubility

A successful drug must exhibit solubility to some extent in both water and lipid environments

Because: • extremely water-soluble drugs may be unable to cross

lipid barriers

• very lipophilic drugs will be trapped in lipid and will not be able to reach their target quickly

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Predicting solubility

• A drug molecule will be soluble in water or in nonaqueous lipid solvent

• A molecule that dissolves in water is hydrophilic (lipophobic)

• A molecule that dissolves in lipid solvent is lipophilic (hydrophobic)

• Solubility in water or lipid depends on functional groups and occurs via intermolecular bonds including

• van der Waals forces • dipole-dipole bonding • ionic interaction • ion-dipole bonding

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Intermolecular bonds

van der Waals also called induced dipole-induced dipole interaction

Dipole-dipole Ionic interaction

Ion-dipole R4N

+------NR3

ion-induced dipole K-I -------I-I

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Intermolecular bonding

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Predicting solubility

• Many drugs are poly-functional and can make all types of intermolecular interactions

• Water/lipid solubility can be predicted by weighing the contribution of each functional group in the compound

• There are two approaches for that:

1. Empirical: based on carbon solubilizing potential of functional groups

2. Quantitative: calculating logP (log of partition coefficient)

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Predicting water solubility – Empirical approach

• A molecule is water soluble if the solubilizing potential of FG exceed the total number of carbon atoms present.

• Note: ionized functional (charged groups) has solubilizing potential of 20 to 30 carbon atoms.

Water solubilizing potential of organic functional groups in

mono- or poly-functional molecules

No of carbon atoms in a molecule

Functional group Monofunctional Polyfunctional

Alcohol 5 – 6 3 – 4

Phenol 6 – 7 3 – 4

Ether 4 – 5 2

Aldehyde 4 – 5 2

Ketone 5 – 6 2

Amine 6 – 7 3

Carboxylic acid 5 – 6 3

Ester 6 3

Amide 6 2 – 3

Urea, carbonate,

carbamate

2

Water solubility is defined as >1% solubility 39

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Is anileridine water-soluble?

Is anileridine hydrochloride water-soluble?

Predicting water solubility – Quantitative approach

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• The partition coefficient will determine the ability of each molecule which tissue it can cross.

• Lipophilic drugs will be able to cross the lipid membranes easily

• Very lipophilic drugs will entrapped in the first lipid tissues that they encounter and they might will not

reach to their target organs.

• Very hydrophilic drugs will be not able to cross the lipid layers such as brain membranes and can be

excreted rapidly

Determination of LogP

• LogP can be determined by two methods:

1.Experimental method using chromatography or

the shake-flask method

• Experimentally measured logP are referred as MlogP

2.Summation of hydrophobic-lipophilic constants

(π) assigned to different functional groups

• Calculated LogP are referred as ClogP

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Calculating logP using π values

• LogP are calculated using the equation

logP = π (π values are the contribution of each functional group)

FG Symbol πaromatic πaliphatic

floro F 0.13 -0.17

chloro Cl 0.76 0.39

bromo Br 0.94 0.60

iodo I 1.15 1.00

alkane C 0.50 0.50

phenyl C6H5 2.13 2.13

acid COOH -0.32 -1.26

1o amide CONH2 -1.49 -1.71

amide NHCOR -0.97 -0.97

ketone COCH3 -0.55 -0.71

nitrile CN -0.57 -0.84

alcohol OH -0.67 -1.12

ether OCH3 -0.02 -0.47

ester COOCH3 -0.64 -0.91

1o amine NH2 -1.23 -1.19

2o amine NHR 0.47 -0.67

3o amine N(CH3)2 -0.18 -0.32

nitro NO2 -0.28 -0.85

IMHB IMHB 0.65 0.65

The π values are obtained as: π = logPx – logPH where, logPx is value for derivative, logPH is value for parent compound

Note: π is +ve for lipophilic group π is -ve for hydrophilic group

Note: LogP also depends on other factors such as the capacity of a group to form intramolecular hydrogen bond (IMHB)

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logP Values for salicylic and p-Hydroxybenzoic acid

Salicylic acid p-Hydroxybenzoic acid

Fragment Value Fragment Value

Phenyl +2.13 Phenyl +2.13

OH -0.67 OH -0.67

COOH -0.32 COOH -0.32

IMHB +0.65

LogP +1.79 +1.14

Prediction Water insoluble Prediction Water insoluble

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Calculate Log P?

0

5

10

15

20

25

100-

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150-

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200-

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300-

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450-

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900-

950

950-

1000

Molecular Weight

fre

qu

en

cy %

3. Molecular size Molecular size is one of the most important

factors affecting biological activity

Most of the oral drugs have molecular weight < 500

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Lipinski’s Rule of five • Drug-like molecule should have the following to enable it to be a drug

molecule:

Molecular weight less than 500

Log P vale less than 5

Hydrogen bond acceptor less than 10

Hydrogen bond donors less than 5

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4. Steric Effects

Bulky substituent appended close to pharmacophore may impede the geometry of interaction between a drug and its receptor

Steric effect is estimated by The Taft steric parameter (Es)

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5. Conformational isomerism Conformational isomers are different conformations for a single molecule result from free

rotation around flexible single bonding

Drugs with multiple conformations are able to bind to different subtypes of a receptor.

For example, acetylcholine binds both muscarinic and nicotinic receptors. It is suggested that gauche binds to nicotinic receptors while anti conformer binds to muscarinic receptor.

Flexible molecules have increased likelihood of drug toxicity due to their ability to interact with undesirable receptor sites.

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6. Stereoisomers

• Stereoisomers are compounds containing the same number of atoms, the same bonding but they differ in the spatial arrangements.

• Are either enantiomers (optical isomers) or diastereisomers

• Enantiomers are molecules that their three-dimentional arrangements are not superimposable and mirror image. They are chiral.

• Diastereoisomers are molecules that are non-superimposable and not mirror image. It can result from the presence of more than chiral center, double bonds and ring systems. They are isomers with different physical and chemical properties.

• Racemate is a 1:1 mixture of enantiomers indicated by (±).

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Optical isomerism

Optical isomers (enantiomers) are molecules that have ability to rotate the plane of polarized light and so they are active.

Only one of the enantiomers will have the maximum affinity to the receptor.

–The higher affinity enantiomer is called the eutomer,

– the lower affinity is called the distomer.

–eudismic index: The ratio of activity of the eutomer and distomer is expressed as:

A

B

C

D

Drug

Biomolecular target

Desired responce

D

B

C

A

No desired resonceSide effects??

EI = log affinityEu – log affinityDist 51

• Recent studies demonstrated that the distomer considered as impurity as it has no meaning to the biological activity as it may produce undesirable side effects and toxicity

• However, some distomer when are metabolized they produces active metabolites that are more potent than both of the enantiomers

• Optical rotation is affected by temperature, solvent and concentration. For example chloramphenicol it is levorotatory in ethyl acetate and dextrorotatory in ethanol.

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Optical isomerism

• To differentiate between enantiomers some nomenclature are used as signs (+/-) or letters (D/L). D indicates that is dextrorotary or (+) and L mean that is Levorotatory or (-).

• However, another system is used now for nomenclature of enantiomers which is Cahn-Ingold-Prelog (CIP) where it assign R and S configuration to the chiral center. Atoms around the chiral center are ranked according to their highest priority. If the sequence of priority is clockwise, it will assign R configuration. If the sequence of priority is anticlockwise, it will assign S configuration.

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Optical isomerism

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Geometric isomerism cis/trans isomers arise due to restricted rotation around double bonds or rigid

systems.

the Cis/Trans (E/Z) isomers of a drug will have different binding affinity to the same receptors

For examples: • cis-diethylstilbestrol has only 7% of the estrogenic activity of trans- diethylstilbestrol

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Stereoisomers and Pharmacological Activity

Pharmacological activity Example

Both show same type and

potency The R and S isomers of chloroquine

Show activity of same

type but one is weaker

Estrogenic activity of Z –diethylstilbestrol is only 7%

that of E-isomer

Show activity of a

different type

S-Ketamine is an anaesthetic but R-Ketamine is a

psychotic

One active the other

inactive S--Methyldopa is a hypertensive but R is inactive

Same activity but different

side effects

Thalidomide: both R & S isomers are sedative but S is

also teratogenic

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