This document discusses the principles of drug design, focusing on the quantitative structure-activity relationship (QSAR) approach that evaluates the impact of hydrophobic, electronic, and steric properties on biological activity. Key concepts include hydrophobicity constants, Hammett substituent constants, and methods for measuring steric effects, all of which inform the rational design of drugs by correlating physicochemical properties with biological activity. Additionally, it highlights techniques like molecular docking and combinatorial chemistry for optimizing drug interactions and developing new compounds.

1. DRUG DESIGNING
BY: Raj K. Prasad (Gold Medalist)
SIP

2. Many physical, structural, and chemical
properties have been studied by the
QSAR approach, but the most common
are hydrophobic, electronic, and steric
properties. This is because it is possible to
quantify these effects.
The QSAR study then considers how
the hydrophobic, electronic, and
steric properties of the substituent’s
affect the biological activity are
called Descriptors.

3. Hydrophobicity is the association of non-polar groups
or molecules in an aqueous environment which arises
from the tendency of water to exclude non-polar
molecules.
The hydrophobic character of a drug is help to how
easily it crosses cell membranes and may also be
important in receptor interactions.
The relative hydrophilic/hydrophobic properties of a
drug are crucial in influencing its solubility,
absorption, distribution, metabolism, and excretion
(ADME).
S
I
P

4. Drugs which are too polar or too hydrophilic do
not cross the cell membranes of the gut wall
easily.
Changing substituents on a drug may well have
significant effects on its hydrophobic character
and which effect its biological activity.
So, it is important to the predicting this
quantitatively.

5.  Partition coefficients can be calculated by
knowing the contribution that various
substituent's make to Hydrophobicity.
 This contribution is known as the substituent
hydrophobicity constant (π) and is a measure of how
hydrophobic a substituent is relative to hydrogen.
 Partition coefficients are measured
experimentally for a standard compound, such as
benzene, with and without a substituent (X).

6.  The hydrophobicity constant (πX) for the
substituent (X) is then obtained using the
following equation:
where PH is the partition coefficient for the standard
compound and PX is the partition coefficient for the
standard compound with the substituent.
•A positive value of π indicates that the substituent
is more hydrophobic than hydrogen;
•A negative value indicates that the substituent is
less hydrophobic.

8.  The partition coefficient P is a measure of
the drug’s overall Hydrophobicity and is,
also measure of how efficiently a drug is
transported to its target and bound to its
binding site.
 The π value measures the
Hydrophobicity of a specific region on
the drug's skeleton.
 In the QSAR equation, indicate, important
hydrophobic interactions involving that
region of the molecule with the binding
site.

9. • Hydrophobic compounds have a high P value, whereas
hydrophilic compounds have a low P value.
•log P values are normally used as a measure of
hydrophobicity.
•Experimental procedures to determine log P include
HPLC

10. It is a measure of the
electron withdrawing
or electron-donating
ability of a substituent,
For examples-
dissociation of a string
of substituted benzoic
acids compared with
the dissociation of
benzoic acid itself.

11.  The Hammett substituent constant (σX) for a
particular substituent (X) is defined by the
following equation:
Substituents such as Cl, CN, or CF3 have
positive σ values
Substituents such as Me, Et, and t -Bu have
negative values of σ. The Hammett
substituent constant for H is zero.

12.  Example-
 Methyl ethanoate is the parent ester and it is
found that the rate of hydrolysis is affected by
the substituent X.
 -I groups reduce the rate of hydrolysis and,
have negative values (σI). For example, methyl,
ethyl, and propyl.

13.  Electron withdrawing groups increase the rate
of hydrolysis and have positive value. For CN,
F, Cl etc.

14. The bulk, size, and shape of a drug will
influence that, the drug how easily can
approach and interact with a binding site.
A bulky substituent may help to
orientation of a drug properly for
maximum binding and increase activity.
Steric properties are more difficult to
quantify than hydrophobic or electronic
properties.

15.  Taft’s steric factor (Es)
 Molar refractivity
 Verloop steric paramete

16.  The value for Es can be obtained by comparing the
rates of hydrolysis of substituted aliphatic esters
against a standard ester under acidic conditions.
Thus,
Where, kx represents the rate of
hydrolysis of an aliphatic ester
bearing the substituent X
and ko represents the rate of
hydrolysis of the reference ester

17.  Substituents which are larger than methyl
reduce the rate of hydrolysis (kx < ko), making
Es negative.
 A disadvantage of Es values is that they are a
measure of an intramolecular steric effect,
 whereas drugs interact with target binding sites
in an intermolecular manner.
 For example, think that Es values for isopropyl,
n-propyl, and n-Bu. The Es value for the
branched isopropyl group is significantly
greater than that for the linear n -propyl group.

18.  It measures the volume occupied by an atom or
a group of atoms.
 The MR is obtained from the following
equation:
where n is the index of refraction,
MW is the molecular weight, and d is the density.
The term MW/d defines a volume and the (n2−1)/(n2 + 2) term
provides a correction factor by defining how easily the substituent
can be polarized.

19.  Its measuring the steric factor using
STERIMOL (computer program ),
 which calculates steric substituent values
(Verloop steric parameters) from standard
bond angles, van der Waals radii, bond lengths,
and possible conformations for the substituent.

20. Ideally, the activities and properties are
connected by some known mathematical
function, F:
Biological activity =
F (physicochemical properties)
Biological activity can be any measure of,
such as C, Ki, IC50, ED50, and Km.

21. This equation shows that activity increases very slightly as the overall
hydrophobicity of the molecule (π sum) increases (the constant 0.14 is
low).
 The (π sum)2 term shows that there is an optimum overall
hydrophobicity for activity.
 The r2 value is 0.834 which is above the minimum acceptable value
of 0.8.

22. The estimation of physico‐chemical properties, biological
activities and understanding the physicochemical
features behind a biological response in drug design.
The rational design of numerous other products such as
surface‐active agents, perfumes, dyes, and fine chemicals.
The identification of hazardous compounds at early
stages of product development, the prediction of toxicity
to humans and environment.

23. The
general
form of
Hansch
equation
is as
follows:
Log BA = a log p + b σ + c Es + constant
(linear)
Log BA = a log p + b (log p)2 + c σ + d Es +
constant (nonlinear)
Hansch model correlates biological activity
with physicochemical properties.
The coefficients (a, b, c, d, and constant) are
determined by multiple regression analysis.

24. The constants k1 – k4 are determined by
computer software in order to get the best-
fitting equation.

25.  A model of the biological target may be built based
on the knowledge of what binds to it, and this
model in turn may be used to design new
molecular entities that interact with the target.
• The functional groups (critical portion of the
structure) of the drug that bind to the receptor
and produced biological activity are termed
“pharmacophores” or “pharmacophoric
groups.”

26. R1 an amino nitrogen is an essential feature of all opioids
because, in cationic conjugate acid form, it permits receptor
anchoring through an essential electrostatic bond with the
Asp residue conserved in all G protein–coupled receptors.
R2 phenolic hydroxyl group or a methoxy ether will be
found at C3 of all marketed multicyclic opioids because of
this phenol is required for binding at μ and kappa (k)
receptors.

27. Docking is the in silico
process by which a
molecular modelling
program fits a molecule
into a target binding site.

28.  Molecular modelling can be used to dock,
or fit, a molecule into a model of its
binding site.
 If the binding groups on the ligand and the
binding site are known, they can be defined
by the operator such that each binding
group in the ligand is paired with its
complementary group in the binding site.

29.  The DOCK program was one of the
earliest programs.
 The Connolly surface is first defined,
then the empty space of the binding site
is defined by identifying a collection of
differently sized spheres which will fill
up the space available and give a
‘negative image’ of the binding site

31.  Combinatorial chemistry is a technique by
which large numbers of different but
structurally similar molecules are produced
rapidly and submitted for pharmacological
assay.
 Combinatorial chemistry helps to produce
compound libraries to screen for novel
bioactivities.

33. These are as follows:
a. A cross-linked,
insoluble polymeric
material should be inert to
the condition of synthesis.
b. The linking substrate
(linker) to the solid phase
that permits selective
cleavage of some or all the
products from the solid
support during synthesis
for analysis of the extent
of reaction and ultimately
to give the final desirable
product.
c. The chemical
protection strategy must
allow selective protection
and de-protection of
reactive groups.

34. Solid-supported reagents are easily removed
from reactions by filtration.
Excess reagents can be used to drive reactions
to completion without introducing difficulties
in purification.
Recycling of recovered reagents is economical,
environmentally-sound, and efficient.

35.  The main problem of solution phase
combinatorial synthesis is to obtain pure
products.
 It was first used for easily synthesized
compound classes (amides, sulfonamides,
ureas, heterocycles).

36. No limitations of the
thermal or chemical
stability of the resin or
the linker.
Synthesis is shorter by
one or two steps.
Reactions in solution
often need considerably
less time.
Reactions can
conveniently be
followed by simple
means (TLC, NMR, UV).