PHR 5201
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.
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
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
Drug Binding
groups
Pharmacological
response Intermolecular
bonds
Binding site
Binding Drug
site
Drug
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
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
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
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
• Water solubility
• Acid / base properties
• Partition coefficient
• (Crystal structure)
• Stereochemistry
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).
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
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
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.
Cl + 0.5
S +0
O (hydroxyl, ether) – 1.0 2 x amines – 2.0
25
Acidic groups Table 2.1 (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!)
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
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
30
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
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
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
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
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
37
Stereochemistry: Space arrangement of the atoms or three-
dimensional structure of the molecule.
CH3 CH3
H H CH3
H3C
OH
OH
2-Hydroxybutane enantiomers (mirror images can not superimposed)
HO OH HO
Cis-diethylstilbestrol Trans-diethylstilbestrol
III- Conformational isomerism and pharmacological
activity
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
CH3 NH3
CH4
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
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
Nonclassical Bioisosteres
1. Exchangeable groups
2. Rings versus noncyclic structures
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?
55