Drug Design

PHR 5201

Drug Structure & Pharmacological

Activity

murad.hossain@northsouth.edu
 Drug Design
Drug design is an effort to develop a new drug by
molecular modification of a lead compound with
maximum effectiveness and greater level of
activity.

Lead compound:
A lead compound is a compound having a
particular biological activity obtained from natural
or synthetic sources.
Example: Sulfanilamide was synthesized in 1908 but its
antibacterial activity for which sulfanilamide is a lead
compound was discovered in 1932. Later numerous
antibiotics have been developed from it.
Sulfanilamide →Sulfamethoxazole
(Lead compound) (Developed drug)
 Sites of Drug Action
1. Enzyme inhibition
 Enzyme inhibition may be reversible or non-reversible; competitive or non-
competitive

2. Drug-Receptor interaction
 A receptor is the specific chemical constituents of the cell with which a drug
interacts to produce its pharmacological effects
This is usually through specific drug receptor sites known to be located on the
membrane

3. Non-specific interactions
 Drugs act exclusively by physical means outside of cells
 These sites include external surfaces of skin and gastrointestinal tract.
 Drugs also act outside of cell membranes by chemical interactions
Neutralization of stomach acid by antacids is a good example
 Mode of Drug Action
 It is important to distinguish between actions of drugs and their effects.

 Actions of drugs are the biochemicals, physiological mechanisms by which the

chemical produces a response in living organisms.

 The effect is the observable consequence of a drug action. For example, the
action of penicillin is to interfere with cell wall synthesis in bacteria and the effect is
the death of bacteria

 One major problem of pharmacology is that no drug produces a single effect.

The primary effect is the desired therapeutic effect.

Secondary effects are all other effects beside the desired effect which may be
either beneficial (good) or harmful (side effects, bad!!).

Drugs are chosen to exploit differences between normal metabolic processes and
any abnormalities, which may be present. Since the differences may not be very
great, drugs may be nonspecific in action and alter normal functions as well as the
undesirable ones, this leads to side effects
The biological effects observed after a drug has been administered are the result
of interaction between that chemical and some part of the organism. Mechanisms of
drug action
 Mechanisms of Actions of Drugs
The fundamental mechanisms of drug action can be distinguished into
following categories

1. Through Enzymes

 Enzymes are very important targets of drug action because almost all
biological reactions are carried out under the influence of enzymes.
Drugs may either increase or decrease enzymatic reactions.
Ex:
• Physostigmine and neostigmine compete with acetylcholine for
cholinesterase

2. Through Receptors

 A large number of drugs act through specific macromolecular

components of the cell, which regulate critical functions like
enzymatic activity, permeability, structural features, template
function
 Receptors and Drug Action
Binding
regions

Drug Binding
groups
Pharmacological
response Intermolecular
bonds

Binding site

Binding Drug

site
Drug

Macromolecular target Macromolecular target

Unbound drug Bound drug

An Introduction to Medicinal Chemistry, Patrick, Third Edition

 Drug-Receptor Interactions
vdw
interaction

Drug
H-bond

Active site
H ionic
O Phe
bond
Ser
CO2

Asp

receptor

• Receptors/enzymes are proteins, so they are amino acids (Asp, Phe, Ser)
• amino acids contain:
 carboxylic acids (ionic interaction)
 amines (ionic interaction)
 hydroxyl (hydrogen bond)
An Introduction to Medicinal Chemistry, Patrick, Third Edition
 Mechanisms of Actions of Drugs
3. Chemical Properties

• The drugs react extracellularly according to simple

chemical reactions like neutralization, chelation, oxidation
etc.

 Aluminium hydroxide neutralizes acid in stomach

Toxic heavy metals can be eliminated by chelating agents

like EDTA, (British anti-Lewisite) BAL, penicillamine etc.
Functional Groups and Pharmacological Activity

 One feature that soon became apparent to the early scientists was
that small changes in structure resulted in significant changes in
biological activity:
H3C
pyrrolidine quaternary CH3 CH3
ammonium phenol N N
pyridine X

N N X

CH3 H3C CH3

N N
HO O OH HO O OH
Nicotine N-Methylnicotine Morphine N-Methylmorphine
(insecticide) (muscle relaxant) (analgesic) (muscle relaxant)

 Crum-Brown & Fraser (1869) postulated that “muscle-relaxant

activity” was related to quaternary ammonium groups (this was later
proved wrong when acetylcholine was discovered)
O CH3

N
CH3 O CH3
CH3
Acetylcholine
(muscle contractant)
 Functional Groups and Pharmacological Activity
 The discovery of acetylcholine (& its activity) prompted questions as to how a given
functional group could have two different biological activities
H3C
pyrrolidine quaternary CH3 CH3
ammonium phenol N N
pyridine X

N N X

CH3 H3C CH3

N N
HO O OH HO O OH
Nicotine N-Methylnicotine Morphine N-Methylmorphine
(insecticide) (muscle relaxant) (analgesic) (muscle relaxant)

O CH3

N
CH3 O CH3
CH3
Acetylcholine
(muscle contractant)

 In the early 20th century, scientists speculated that this could be achieved if “drug
receptors” were present

 If acetylcholine interacts with its receptor, then molecules that are

structurally similar to acetylcholine would also interact with the receptor
11
Drug Structure and Mechanism of action
Structure and Physiochemical properties

• Water solubility
• Acid / base properties
• Partition coefficient
• (Crystal structure)
• Stereochemistry

Identification of acidic / basic functional groups

pKa determines degree of ionization different places
in the body
 Lipinski’s Rule of Five

• Rule of thumb for druglikeness (orally active in humans)

(4 rules with multiples of 5)
– mass of 500 Daltons or less
– 5 hydrogen bond donors or less
– 10 hydrogen bond acceptors or less
– A partition coefficient (logP) value between -5 and 5

15
 Water Solubility
 Given that we are ~75% water, the solubility of a
drug in water directly affects the route of
administration, distribution, and elimination
(ADME).

 The most important two key factors that

influence this are:

 Hydrogen bonding: more H-bonds => 

solubility
 Ionisation: dissociable ions =>  solubility
16
Water Solubility

17
 Water Solubility
The more H-bonds possible - the more water sol.

H H
O O H
H
H H O

Alchohol O 3 H-Bonds H H
R H
Primary amine R N H O
3 H-Bonds
O H
H H
H H
O
H H
O O
H H

Aldehyde / ketone O 2 H-Bonds

R' H
R R' Secondary amine R N H O
2 H-Bonds
H

H H H H
O O O
H H
R'
Ester O 3 H-Bonds 1 H-Bonds
Secondary amine R N R''
R
R O
H H
H H O
O

18
 Physical Properties
(water and lipid solubility)
• Partition coefficient
– lipophilic vs. hydrophilic character of drug
– determines water solubility of drug substances
– affects drug distribution
– confers target-drug binding interactions

[c o m p o und ] o
P
[ c o m p o und ] w 19
Predicting Water Solubility
 Empirical Approach
 Analytical Approach

20
 Predicting Water Solubility
Empirical Approach
 Lemke has developed an approach to predicting water solubility based upon the
“solubilising potential” of various functional groups, versus the number of carbons
Functional Monofunctional Polyfunctional
Group molecule molecule
alcohol R OH 5 to 6 carbons 3 to 4 carbons

phenol Ar OH 6 to 7 carbons 3 to 4 carbons

ether R O R 4 to 5 carbons 2 carbons

aldehyde O 4 to 5 carbons 2 carbons

ketone R R' 5 to 6 carbons 2 carbons

amine R NH2 6 to 7 carbons 3 carbons

carboxylic acid 5 to 6 carbons 3 carbons

O
ester (R' = OR) 6 carbons 2 to 3 carbons
R R'
amide (R' = NHR) 6 carbons 2 carbons

21
 Given that most drugs are polyfunctional, the second column is most relevant
 Predicting Water Solubility
The Empirical Approach – a working example
alkyl amine
(3 carbons)
N
CO2CH2CH3
aryl amine
(3 carbons) ester
H2N
(3 carbons)

Anileridine
(Narcotic analgesic)
 We get a total “solubilising potential” of 9 carbons using this theory.

 Since the molecule contains 22 carbons, it suggests that the molecule is

insoluble in water (USP has water solubility listed as <1g per 10,000ml)

 However, if we make the hydrochloride salt, then the compound becomes

water soluble
Lemke estimates that a charge (either anionic or cationic)
contributes a “solubilising potential” of between 20 and 30
22
carbons
 Predicting Water Solubility
Analytical Approach
 The alternative approach for predicting water solubility utilises the
“logP” of molecules

 Essentially, logP is a measure of lipophilicity (hydrophobic)

properties of a molecule

 It is determined by measuring the “partition coefficient” between

water and octanol for a given molecule (i.e. the solubility of the
compound in octanol versus the solubility of the compound in water)
 Octanol is used as a mimic of the characteristics of a lipid
membrane (polar at one end, long hydrocarbon chain at the other)
LogP is calculated by adding the contributions from each
functional group in the molecule
 A hydrophobic substituent constant π has been assigned to most
organic functional groups, such that LogP = ∑ π (fragments)
23
 Predicting Water Solubility
Analytical Approach-a working example
Fragment π value N
C (aliphatic) + 0.5 CO2CH2CH3

Phenyl + 2.0 H2N

Cl + 0.5
S +0
O (hydroxyl, ether) – 1.0 2 x amines – 2.0

N (amine) – 1.0 9 x aliphatic carbon + 4.5

IMHB + 0.65 2 x phenyl rings + 4.0

O=C–O (carboxyl) – 0.7 1 x ester – 0.7

O=C–N (amide) – 0.7 logP + 5.8

 Water solubility is defined (by the USP) as greater than 3.3%, or a logP <+ 0.5
 Therefore, anileridine, with a logP greater than + 0.5 is considered insoluble
 The “ionisation state” of a molecule not only influences water solubility, but also its
ability to cross biological barriers or be absorbed
24
 See Fig. 2.15, page 38, Foye’s.
 Physiochemical Properties
 Acid-Base: Conjugate pair theory
 Common acidic and basic functional groups
• W&L Table 2.1 and 2.2 respectively
• Shows acids and their conjugate bases together
with pKa
 Be able to identify these from structures

25
Acidic groups Table 2.1 (page 29)

Acidic groups (page 29)

26
Basic groups Table 2.2 (page 30)

27
Neutral groups Table 2.3 (page 30)

28
 Physiochemical Properties – Acids & Bases
 The human body is composed of ~75% water (55 L of water)
 For an average drug (MW ~200; dose = 20 mg), this equates to a drug concentration of
~1.8 x 10-6M (i.e. a very dilute solution!)

 For dilute solutions we use the Brönsted–Lowry theory to predict the

behaviors of acids & bases
 An Acid is any substance capable of yielding a proton (H+)
 A base is any substance capable of accepting a proton (H+)

CH3COOH + H2O CH3COO + H3O

acid base conjugate conjugate
base acid

CH3NH2 + H2O CH3NH3 + HO

base acid conjugate conjugate
acid base

29
 Physiochemical Properties – Acids & Bases
 Some drugs have both acidic and basic functional groups, and therefore can act as a
base, an acid, or amphoteric (= both acidic & basic properties)
neutral
Ciprofloxacin

aryl amine O acidic

weakly basic F CO2H

alkyl amine N N
basic aromatic amine
HN weakly basic

 The location of the compound in the body will determine the overall charge
of the compound

O O O
F CO2H F
O

N N N N
H H
N N
H H
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stomach (pH 1.0 to 3.0) Duodenum (pH ~ 4)
 Relative Acid Strength (pKa)
(Henderson–Hassalbach)
 Henderson-Hasselbach Equation relates pH and pKa (acid strength)

[c o nj. b a s e ]
p H  p K a  lo g
[ a c id ]
 This equation (the Henderson–Hassalbach eqn) allows us to calculate the percent
ionisation of a given molecule at a given pH

 since pKa is a constant for a given molecule, at a known pH (e.g. physiological) the
concentration of the acidic and basic forms of a given drug will be able to be
calculated

But why is this important??

 Percent ionisation (clue to absorption of drug and activity/interactions)

31
 Relative Acid Strength (pKa)
 Look at the sulphonamides (antibacterial)
 Why is the following true?
lipo- relative half
pKa solubility activity life
R=H 10.5 10.5 1 9
O
sulfanilamide
H 2N S N R N
H R= 6.4 26 140 17
O N
sulfadiazine

 These compounds are only active in their ionised forms

 Despite only minor differences in half-life and lipo-solubility, there is a huge difference in
activity

 This is due to their respective pKa values:

 For sulfadiazine, at pH 7.4 it is ~80% ionised
 For sulfanilamide, at pH 7.4 it is only 0.03% ionised

 The difference in pKa is due to the electron withdrawing nature of the sulfonamide nitrogen
substituent, thereby stabilising the ionised form:

O H O N O N
N -H+
NH2 S N NH2 S N NH2 S N
32
O N O N O N
 Ionisation of Drugs
 For an acid drug:

100
% io nis a tio n  ( pK a  pH )
1  10

 For a basic drug:

100
% io nis a tio n  ( pH  pK a )
1  10
33
 Example: %ionisation for aspirin
• pKa of aspirin (acetylsalicylic acid) is 3.5
• Physiological pH = 7.4
CO2H CO2
O O
For an acid drug O O
CH3 CH3
100
% io nis a tio n  ( pK a  pH )
acetylsalicylic acid
1  10 (Aspirin)

100 100
% ionisation  ( 3 .5  7 .4 )

1  10 1  10 ( 3.9 )
100 100
 
1  0 .000126 1 .000126
 99 .99 % 34
 Rule of Thumb (acids)
• 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 • pH = pKa+ 4

• Physiological pH = 7.4

35
%ionisation= 99.99%
 Rule of Thumb (bases)
• 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
OH OH
NH3
NH2 H
• pH = pKa- 2
CH3 CH3
phenypropanolamine

• pKa of phenylpropanolamine is 9.4

• Physiological pH = 7.4
%ionisation= 99% ionised
36
Stereochemistry and Biological
Activity

37
Stereochemistry: Space arrangement of the atoms or three-
dimensional structure of the molecule.

Stereochemistry plays a major role in the pharmacological

properties because:

(1) Any change in stereospecificity of the drug will affect its

pharmacological activity
(2) The isomeric pairs have different physical properties
(partition coefficient, pka, etc.) and thus differ in
pharmacological activity.

The following steric factors influence pharmacological

activity:
● Optical and geometric isomerism
● Conformational isomerism
● Isosterism and bioisosterism
 Structural features of drugs and their
pharmacological activity

I-Optical and geometric isomerism and pharmacological

activity

Optical isomers are compounds that contain at least one

chiral carbon atom or are compounds that differ only in
their ability to rotate the pollarized light.

The (+) or dextrorotatory: isomer rotates light to the right

(clockwise). The (-) or levorotatory: isomer rotates light to
the left (counterclockwise).
 I-Optical and geometric isomerism and
pharmacological activity

CH3 CH3
H H CH3
H3C
OH
OH
2-Hydroxybutane enantiomers (mirror images can not superimposed)

Enantiomers (optical isomers) can have large differences

in potency, receptor fit, biological activity, transport and
metabolism.
For example, levo-phenol has narcotic, analgesic, and
antitussive properties, whereas its mirror image, dextro-
phenol, has only antitussive activity.
II-geometric isomerism and pharmacological activity

Geometric isomerism (cis-trans isomerisms).

Occur as a result of restricted rotation about a chemical bond, owing
to double bonds or rigid ring system in the molecule.
They are not mirror images and have different physicochemical
properties and pharmacological activity. Because different distances
separate the functional groups of these isomers.
They generally do not fit to the same receptor equally well and if these
functional groups are pharmacophores the isomers will differ in
biologic activity.
For example, cis-diethylstilbestrol has only 7% of the oestrogenic
activity of trans- diethylstilbestrol OH

HO OH HO

Cis-diethylstilbestrol Trans-diethylstilbestrol
III- Conformational isomerism and pharmacological
activity

Conformational isomersim is the non-identical space arrangement of

atoms in a molecule, resulting from rotation about one or more single
bonds.
Almost every drug can exist in more than one conformation and thus the
drug might bind to more than one receptor but a specific receptor site
may bind only to one of many conformations of a drug molecule.
For example, the trans conformation of acetylcholine binds to the
muscarinic receptor, where as the gauche conformation binds to the
nicotinic receptor.
+ +
N (CH3) 3 N (CH3) 3

H H H H
H H
H OAc
OAc H
Trans Gauche
Conformations of acetylcholine 42
Isosterism and Bioisosterism

43
 Isosterism and Bioisosterism
 A poor “drug profile” includes issues such as bioavailability,
unwanted side effects, inability to cross biological barriers, poor
pharmacokinetics.
These undesirable features could be due to specific functional
groups in the molecule.
 Modify this molecule to reduce these undesirable features
WITHOUT losing the desired biological activity with other groups
having similar properties is known as ISOSTERIC or
BIOISOSTERIC replacement.
In 1919 Langmuir first developed the concept of isosterism to
describe the similarities in physical properties among atoms
(same number of valence electrons O and S).
 In 1925 Grimm developed his hydride displacement law
(illustration of similar physical properties among closely related
functional groups)
Thus, NH2 is considered to be isosteric to OH, SH, CH3)
 Grimm’s isosteres - 1925
C N O F Ne

CH NH OH HF

CH2 NH2 OH2

CH3 NH3

CH4

 Descending diagonally from left to right in the table H atoms are

added to maintain the same number of valence electrons for each
group of atoms within a column.

 Each member of a vertical group is isoelectronic

 Isosterism
 Initially this concept related to the notion that different functional groups
have the same number of valence electrons

 NH2 and OH are considered to be isosteric to each other

 Both groups are able to participate in hydrogen bonding interactions

 However, NH2 is basic at physiological pH, which means that changing an

OH to an NH2 would give the molecule a positive charge at physiological pH (&
therefore very different pharmacokinetics)

 Some isosteric replacements do work well (e.g. replace benzene with

pyridine), but it is difficult to generalise between different biological systems

benzene pyridine
 Isosterism and Pharmacological Activity
(example)
 “isosteric replacement” replacement of functional groups, where the chemical group
considered to be important for activity is replaced by a different chemical group which
has the “same” properties

O H O H
H2N O H2N S N R
O
PABA sulfonamide

O O
H2N H2N S NHR
O O
H-bond v.d.w. H-bond v.d.w.
ionic ionic

enzyme active site enzyme active site

 These “isosteres” are important when considering issues such as water solubility,
acidity / basicity, lipophilicity, etc, since sometimes compounds with excellent biological
activity have a poor “drug profile”
 Bio-isosterism
 This process attempts to overcome the limitations of isosteric
replacement by considering not just the similarity in chemical
structure between functional groups, but to also look at the
biological effects

• Friedman definition “bio-isosteres are functional groups or

molecules that have chemical and physical similarities producing
broadly similar biological properties”

• Burger definition: “bio-isosteres are compounds or groups that

possess near equal molecular shape and volumes, and with exhibit
similar physical properties such as hydrophobicity”.

 The key point is that the same pharmacological target is influenced

by bioisosteres as agonist or antagoinist.

There are two general types of “bio-isosteres”

• Classical and non-classical

 Classical Bioisosteres

1. Monovalent atoms and groups (C, N, O, S)

2. Divalent atoms and groups (R-O-R, R-NH-R, )
3. Trivalent atoms and groups (R-N=R, R-CH=R)
4. Tetrasubstituted atoms ( =C=, =N=, =P=,)
5. Ring equivalents

Nonclassical Bioisosteres

1. Exchangeable groups
2. Rings versus noncyclic structures

The nonclasical bioisosteres do not rigidly fit the steric and

electronic rules of the classical bioisosteres
 Bio-isosterism… Classical
 (Monovalent bio-isosteres)
 A common replacement is F instead of H (in the development of antineoplastic
agent 5-fluorouracil from Uracil) O O
H
 van der Waal’s radii: F = 1.35Å; H = 1.2Å HN HN
F

 (therefore very similar steric demand)

O N O N
 The only real difference is electronegativity H H
uracil 5-fluorouracil

 Tetravalent bio-isosteres of -tocopherol:

 -tocopherol (when X= C14H29) was found to accumulate in heart tissue

 All bio-isosteric analogues (when X= NMe3, PMe3 Or SMe2) were found to produce
similar biological activity Me
HO X = NMe3

X X = PMe3
Me O
Me
Me X = SMe2

-tocopherol X=C14H29
Bio-isosterism… Classical
Examples of Bio-isosteres (Classical)
O O
H F
HN HN

O N O N
H H

S N
N H
O OH
O
OH
X N
N H O
N N
H X = OH: Folic Acid
H2N N N X = NH 2: Aminopterin 52
(basis of methotrexate)
 Bioisosterism….Non-Classical
 Replace a functional group with another group which retains the
same biological activity
 Not necessarily the same valency
 But following characteristic feature:
 Electronic properties
 Physicochemical properties,
 Spatial arrangement,
 Functional moiety for biological activity.

Example: N
antipsychotics N
Et
Et

N
N Pyrrole ring =
O H
H bio-isostere for
OMe
OMe
amide group
EtO2S
EtO2S
DU 122290
Sultopride

Improved selectivity
for D3 receptor
An Introduction to Medicinal Chemistry, Patrick, Third Edition
over D2 receptor
 References
– Foye, Lemke & Williams, 6thed, Chapter 2
– An Introduction to Medicinal Chemistry, Patrick L. G., 4th
ed
ANY QUESTIONs?

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