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Drug Design
(Physicochemical Properties in
relation to biological activities)
By
Nohad A Atrushi
9/3/2017
Drug – Receptor Interactions forces
The some binding forces involved as when
simple molecules interact will be involved in
interaction of drug with a functional or
organized group of molecules , which may be
called " biologic receptor site " .
# The forces involved in Drug-Receptor
interaction are collected in table 2-8 :• In most cases, it is desirable that the drug leaves
the receptor site when the concentration
decrease in the extracellular(EC) fluid . therefore ,
most useful drugs are held to their receptors by
ionic or weaker bonds , when relatively long
lasting or irreversible effects are desirable (ex.
antibacterial, anticancer ) ,Drugs that form
covalent bonds are effective & useful .
• The alkylating agents, such as the nitrogen
mustards (ex. mechlorethamine ) used in cancer
chemotherapy given an example of drugs that act
by formation of covalent bond .
•
• These are believed to form the reactive
immonium ion intermediate, which alkylate &
thereby link together proteins nucleic acids ,
preventing their normal participation in cell
division .
FIG. 2-7 . formation of the immonium cation & it's alkylation of
protein or nucleic acid. R. Ŕ= free amino groups of proteins ,
adenyl or phosphate groups of nucleic acids .
H3C
CH2CH 2Cl
CH2CH2Cl
CH 2CH 2Cl
H3C
N
N
RH
CH2
H3C
N
CH2CH 2R
CH2
CH 2CH 2Cl
Alkylated Protein or
Nucleic Acid
Immonium Ion
Mechlorethamine
CH 2CH 2R'
H3C
CH 2
R'H
N
H3C
CH 2CH 2R
Cross-linked Protein or
Nucleic Acid
N
CH 2
CH 2CH 2R
• Covalent bond formation between drug and
receptor is the basis of "Baker's concept" of
active site directed irreversible inhibition.
Enzymes inhibitors has supported
experimental this concept .
• Compounds studied posses appropriate
structural features for reversible & highly
selective association with an enzyme.
If , in addition , the compounds carry reactive
groups capable of forming covalent bonds ,
the substrate may be irreversibly bond to the [
drug-receptor ] complex .
Cl
Cl
O
H
C
O
CH 2
CH 2COOH
H
H
H
C
N
CH 3
CH 2CH 3
( Ethacrynic acid )"diuretic"
( selegiline)
CH 2C
CH
The diuretic drug , ethacrynic acid is an α , β unsaturated ketone , thought to act by covalent
bond formation with sulfhydryl groups (thiol
group) of ion transport systems in the renal
tubules .
Another examples of drugs which covalently binds
to the receptor is selegiline which is an inhibitor
of monoamino oxidase B (MAOB inhibitor) .
Other examples of covalent bond formation between drug &
biologic receptor site include the reaction of arsenicals &
mercurials with cysteine thiol groups (- SH ), also the
acylation of bacterial cell wall(C.W) constituents by penicillin
& the phosphorylation of the serine hydroxyl moiety at the
active site of cholinesterase by the organic phosphate .
The most important to patient is to know that :- is desirable that
most drug effects be reversible . for this to occur , relatively
weak forces must be involved in the [drug –
receptor]complex, at the same aim be strong enough that
other binding site will not competitively deplete the site of
action .
H-bond : many drugs posses groups , such as carbonyl ,
Hydroxyl , amine & imino which the first structure capabilities
of acting as acceptor or donors in the formation of Hbond .
* Vander waal’s forces:- are attractive forces created by the
polarizability of molecules & are exerted when any two
uncharged atoms approach each other very closely .
* Hydrophobic bond :- is a concept used to explain attraction
between nonpolar regions of the receptor & the drug.
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
[compound]o
P
[compound]w
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Water Solubility
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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
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Predicting Water Solubility
 Empirical Approach
 Analytical Approach
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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
Group
alcohol
phenol
R OH
Ar
OH
Monofunctional
molecule
Polyfunctional
molecule
5 to 6 carbons
3 to 4 carbons
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
R'
5 to 6 carbons
2 carbons
NH2
6 to 7 carbons
3 carbons
5 to 6 carbons
3 carbons
6 carbons
2 to 3 carbons
6 carbons
2 carbons
ketone
R
amine
R
carboxylic acid
ester
amide
O
(R' = OR)
(R' = NHR)
R
R'
 Given that most drugs are polyfunctional, the second column is most relevant
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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 carbons
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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)
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Predicting Water Solubility
Analytical Approach-a working example
Fragment
π value
N
CO2CH2CH3
C (aliphatic)
+ 0.5
Phenyl
+ 2.0
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
H2N
 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
 See Fig. 2.15, page 38, Foye’s.
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Stereochemistry and Biological
Activity
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Stereochemistry and Biological Activity
 The physicochemical properties of a drug are not only influenced by which
functional groups are present, but also by the spatial arrangement of groups.
 The spatial arrangement of groups is especially important when dealing with
biological systems, since receptors are susceptible to the shape of a molecule.
 Stereoisomers contain the same number and kinds of atoms, the same arrangement
of bonds, but a different spatial arrangement of atoms.
 A carbon atom with four different substituents is an asymmetric
molecules.
 Stereochemistry is primary:
– Optical isomerism (Enantiomers, Diastereomers)
– Geometric isomerism
– Conformational isomerism
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Designation of stereoisomerism
 Cahn, Ingold & Prelog (1956) devised a system of nomenclature for stereoisomer
Prioritise atoms around a chiral centre, based upon the atomic weight of the atom
1
anti-clockwise S
4
2
3
 Once you have assigned priority from 1 (= highest) to 4 (= lowest), then “look from the
chiral centre towards the lowest priority and count from 1 to 3
 If
you count clockwise it is “R”
 If
you count anticlockwise it is “S”
4
1
R
2
3
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Optical Isomers & Biological Activity
 Whilst enantiomers have identical physical properties, they can have very
different biological properties (e.g. (+)-asparagine is sweet, whilst
(–)-aspargine is tasteless). This was one of the earliest observation by in
1886).
 Easson-Stedman hypothesis states that the more potent enantiomer must be
involved in a minimum of three interactions with the receptor and that the less
potent enantiomer only interacts with two sites
This difference is due to the asymmetry of receptor – ligand interactions
D
A
A
D
C
B
C
B
biological
receptor
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Selective Reactivity - Enantiomers
 R-(-)-epinephrine vs. S-(+)-epinephrine
– each enantiomer maps to the receptor site differently – (see Foye,
Fig 2.19, page 41)
S, Epinephrine
R, Epinephrine
H3C
N
H
H

OH
OH
H3C
H
OH
H
OH

N
H
H
OH
OH
Flat area
Flat area
Anionic site
HB
Receptor
Anionic site
HB
Receptor
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Diastereomers – Asymmetric Centres
Diastereomers:
 Stereoisomers with the same number and kinds of atoms, but in a different
spatial arrangement (any stereoisomers compound that is not an enantiomer)
 These compounds have different physical and chemical properties
 These arise from compounds possessing two or more asymmetric centres
 Consider isomethadol
H
• 2 asymmetric carbons
• 4 isomers (2 pairs of enantiomers)
• only the (3S,5S)-isomer has analgesic activity.
C (S)
C
H
N
(S)
OH
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Diasteroemers & Biological Activity
 Most drugs contain more than one chiral centre, so therefore
diastereomers become important.
 Two chiral centers: up to four stereoisomers, consists of two sets of
enanatiomeric pairs. For each enantiomeric pair there is inversion of
both chiral ecnters, while in the disteroemers there inversion in only
one chiral center.
H OH
HO H
(R) (S)
NHMe
(S) (R)
enantiomers
H Me
Me H
(+)-ephedrine
(–)-ephedrine
diastereomers
diastereomers
HO H
(R) (R)
NHMe
H OH
NHMe
H Me
(–)-pseudoephedrine
enantiomers
(S) (S)
NHMe
Me H
(+)-pseudoephedrine
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Enantiomeric Pair Differences
• Some examples
– Isomethadol (cf methadone) - analgesic
– Acetylisomethadol - transformation induced
– Etomidate - nonbarbiturate hypnotic
– Ibuprofen - NSAID/Analgesic
– Naproxen - NSAID/Analgesic
– Verapamil - Ca channel blocker
– Warfarin - anticoagulant
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Geometric isomers & biological activity
 Geometrical isomerism (= restricted rotation)
H
Me
H
H
Me
Me
cis- or Z-isomer
Me
Z- comes from German “Zusammen”
(= together)
H
E- comes from German “Entgegen”
(= opposite)
trans- or E-isomer
• Sometimes E- and Z- becomes difficult to determine when it is less obvious
which substituents are the highest priority:
N
1
1
2
2
MeO
N
1
N
2H
2
H
1
triprolidine
N
MeO
(a histamine antagonist)
The
key here is to assign the two groups on each side of the double bond,
and then “simply” see if the two highest priority groups are on the same
side or opposite sides
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Geometric isomers & biological activity
 cis/trans isomers have different physical properties
 distribution in biologic system varies
– generally leads to distinct biological activity
• But … difficult to correlate activity differences with
stereochemistry alone
– eg different pKas of isomers => different levels of ionisation
and hence => differing penetration or absorption
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Cis-trans Spatial arrangement of pharmacophores
• eg Diethylstilbestrol (W&L p62)
– trans isomer more active than cis
OH
HO
OH
HO
trans-diethylstilbestrol
cis-diethylstilbestrol
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Conformational Isomers
 Conformational isomerism - Eliel’s definition
 “ ... the no identical spatial arrangement of atoms in a molecule,
resulting from rotation about one or more single bonds.”
 Involves both acyclic and cyclic drug molecules
– acyclic - flexible - Newman and sawhorse models
– cyclic - rigid - chair/boat model of conformers
 cyclic molecules of more interest medicinally
H3C
H3C
N
*
O
*
CH3
CH3
O
Acetylcholine
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Conformational Isomers
 Endogenous lead compounds often simple and flexible
(e.g.
adrenaline)
 Fit several targets due to different active conformations
(e.g. adrenergic receptor types and subtypes)
single bond
rotation
+
+
Flexible
chain
Different conformations





Rigidify molecule to limit conformations - conformational restraint
Increases activity (more chance of desired active conformation)
Increases selectivity (less chance of undesired active conformations)
Disadvantage:
Molecule more complex and may be more difficult to synthesise
An Introduction to Medicinal Chemistry, Patrick, Third Edition
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Conformational Isomers (Epinephrine)
H
NH2Me
H
O
O
NH2Me
H
H
BOND
ROTATION
II
I
O 2C
H
H
NH2Me
O
O
O H
NH2Me
H
RECEPTOR 1
An Introduction to Medicinal Chemistry, Patrick, Third Edition
O 2C
O H
H
RECEPTOR 2
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Rotatable bonds
Target inetraction site
An Introduction to Medicinal Chemistry, Patrick, Third Edition
46
Rotatable bonds
Target interaction site
An Introduction to Medicinal Chemistry, Patrick, Third Edition
47
Rotatable bonds
Target interaction site
An Introduction to Medicinal Chemistry, Patrick, Third Edition
48
Rigidification
Methods - Introduce rings
Bonds within ring systems are locked and cannot rotate freely
rotatable bonds
fixed bonds
H
H
O
O
NHMe
NH2Me
H
FLEXIBLE
MESSENGER
An Introduction to Medicinal Chemistry, Patrick, Third Edition
RIGID MESSENGER
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Isosterism and Bioisosterism
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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)
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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
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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
N
benzene
pyridine
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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
H2N
O H
O
H2N
S
N
R
O
PABA
sulfonamide
O
O
H2N
H-bond
H2N
v.d.w.
O
enzyme active site
H-bond
ionic
S
v.d.w.
NHR
O
ionic
enzyme active site
 These “isosteres” are important when considering issues such as water solubility,
acidity / basicity, lipophilicity, etc, since sometimes compounds with excellent
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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
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Bio-isosterism… Classical
 (Monovalent bio-isosteres)
 A common replacement is F instead of H (in the development of
agent 5-fluorouracil from Uracil)
O
 van der Waal’s radii: F = 1.35Å; H = 1.2Å
 (therefore very similar steric demand)
 The only real difference is
O
O
H
HN
electronegativity
antineoplastic
F
HN
N
H
uracil
O
N
H
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
X = NMe3
HO
X
Me
O
Me
Me
-tocopherol
X = PMe3
X = SMe2
X=C14H29
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Examples of Bio-isosteres (Classical)
O
O
H
HN
O
N
H
F
HN
O
N
H
N
H
S
N
O
H2N
N
N
OH
OH
N
X
N
O
N
N
H
H
O
X = OH: Folic Acid
X = NH2: Aminopterin
(basis of methotrexate)
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Bioisosterism….Non-Classical
 Replace a functional group with another group which retains
the same biological activity
 Not necessarily the same valency
Example:
antipsychotics
N
Et
N
Et
O
N
N
H
H
OMe
OMe
Pyrrole ring =
bio-isostere for
amide group
EtO2S
EtO2S
Sultopride
An Introduction to Medicinal Chemistry, Patrick, Third Edition
DU 122290
Improved selectivity
for D3 receptor
over D2 receptor
58
Take Home??
 Relationships of Functional Groups to Pharmacological Activity (SARs)
 Physiochemical Properties of drug molecules
Acid - base properties of drug molecules
pH and pKa (Henderson-Hassalbach Equation)
ionisation and absorption
Water and lipid Solubility (hydrogen and ion bonds)
Predicting water solubility
• Empirical approach
• Analytical Approach
 Partition coefficient
• absorption/distribution





 Stereochemistry and pharmacological activity
 Optical isomerism (enantiomers and distereomers)
 Conformation isomers
 Geometric isomers (cis and trans)
 Isosterism and Bioisosterism
 drug design
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ANY QUESTIONs?
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