NSCBIP/Sem-VI/Medicinal Chemistry III/ Introduction to Drug Design & QSAR /Mr.

Samiran Sadhukhan/2024

Introduction to Drug Design

Syllabus:
• Introduction to Drug Design Various approaches used in drug design.
• Physicochemical parameters used in quantitative structure activity relationship (QSAR)
such as partition coefficient, Hammet’s electronic parameter, Taft's steric parameter and
Hansch analysis.

Introduction
• The drug discovery or design of new drugs requires a rational process along with the synthetic
techniques, methods of administration, development of tests, and further procedures to establish
pharmacodynamics and their toxicological assessment.
• The diversity in synthetic chemistry is ever-increasing due to the increase in the number of
chemical compounds, which made it necessary to find out the possibilities for the development
of new, logical, and scientific approaches in the discovery of new molecules or drugs, which
came to be known as drug designing.
• Drug design is an integrated advancing discipline, in which a biologically active molecule is
produced by chemical synthesis followed by an evaluation of its activity and toxicological
studies with the limitation of trial-and-error screening.
• In the broader sense, it implies the random evaluation of congeners produced from the lead
molecule either by implementing tailor-made techniques or applying the basic concepts of
physicochemical properties to produce an able drug or medicine for human use.
• Drug discoveries made by accident and intelligence, are regarded as Random drug discovery (or
serendipitous drug discovery). Over the last 25 years, with technological advances, the process
of drug discovery evolved into a system where a new lead molecule undergoes full development
into a drug regarded as Rational drug discovery. Today, nearly all pharmaceutical companies
follow this common technology process for discovering new drugs.
Design of analogs and prodrugs
• Drug design involves the development of analogs by some chemical modifications from the lead
molecule or a parent compound by modifying the carbon skeletal transformation or by the
synthesis of compounds of the same nucleus with various substitutions. Analogues can also be
synthesized by changing the position of the substitution group. For example, the synthesis of
trans-diethylstilboestrol by the modification of oestradiol produced better oestrogenic activity
than the latter one.
• The term prodrug means that a pharmacologically active substance is administered in an inactive
(or significantly less active) form. It will undergo the metabolism in vivo as an active metabolite.
The prodrugs are discovered by the screening of active metabolites after in vivo
biotransformation that is formed from parent compounds. For example, phenylbutazone is
transformed into oxyphenbutazone by a hydroxylation reaction mediated by phase I
(nonsynthetic) metabolic reaction.
Design of lead and lead discovery
The concept of lead discovery envisages two investigational processes:
1. Exploration of leads: Search for new molecules.
2. Exploitation of leads: Assessment, chemical modeling, and extension of leads.
Drug discoveries without a lead are quite a few. The most prominent examples are the penicillium
and Librium.

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NSCBIP/Sem-VI/Medicinal Chemistry III/ Introduction to Drug Design & QSAR /Mr. Samiran Sadhukhan/2024

Approaches to lead discovery

The lead identifications require a series of biological evaluations of the lead molecules. Once, after
the identification, it can be structurally modified, the potency and the activity can be improved.
Random Screening
The entire synthesized compounds or any chemical constituents obtained from natural products are
evaluated in a series for their biologically active components. Thus, random screening may produce
unexpected active medicines. Antibiotics such as streptomycin and tetracycline, and fungal
metabolites such as lovastatin and cyclosporine were found through this method. This approach
needs more manpower, and it is expensive and time-consuming and the success rate is considerably
low.
Nonrandom Screening
In this method, only compounds that possess similar structural skeletons were evaluated from their
particular properties.
Pharmacokinetic Studies
Biotransformation occurs as the fate of metabolizing enzymes. To develop new leads, the
metabolites or bio-transformed compounds are studied for their properties, and such studies are
expected to assess the activity from a comparison with the parent molecule. For example, the
discovery of sulphanilamide is reported through the metabolic studies of prontosil.
Pharmacodynamic Studies
The effects apart from the therapeutic actions, that is, side effects may lead to the finding of a new
molecule with some appreciable structural modification. For example, sulphonamide used
specifically for the treatment of typhoid lowered the blood sugar levels drastically. This exerted
action led to the finding of aryl sulphonyl thiourea moiety responsible for the lowering of blood
glucose levels.
Drug Design Through Disjunction
Disjunction comes into the systemic formulation of analogs of a prototype agent, generally, towards
structurally simpler products, which may be carried as quasi-replicas or partials of the prototype
agent. This is employed by various methods, as listed below.
Unjoining of certain bonds
• Substitution of an aromatic cyclic system for saturated bonds
• Elimination of the size of the hydrocarbon portion of the parent molecule
• Decyclization of any ring system
• Cyclization of hydrocarbon chains
For example, oestrogenic study of oestradiol through drug design by disjunction produced
successful molecules of trans-diethylstiboestrol. The activity is possibly dependent on the distance
between two hydroxyl groups.

Molecular hybridization of drug design

Molecular hybridization essentially embodies the synthesis of strategically designed new breeds
of bioactive agents from two or more compounds having different characteristic features with the
aid of covalent bond synthesis.

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NSCBIP/Sem-VI/Medicinal Chemistry III/ Introduction to Drug Design & QSAR /Mr. Samiran Sadhukhan/2024

For example, the hybridization of acetylsalicylic acid (antipyretic) and quinine (antimalarial) to
lose a molecule of water to form a hybridized molecule for a potent antimalarial drug with
substantial antipyretic and analgesic activity.

Rational approach to drug design

There are many approaches to drug designing about physiochemical parameters and electronic
features taken into consideration for designing a drug. These are as follows:
1. Approach with quantum mechanics: This, also known as wave mechanics, comprises the
fundamental physical properties of a molecule. These include the properties of protons, neutrons,
and electrons, which are explained by quantum mechanics. The basis of drug molecule nature is
altered by chemical alterations of the electronic features.
2. Approach with molecular orbital theory: This approach depicts the change in properties that shall
be made by the alteration of orbits. Based on this, the electrons present in the molecules are linked
with orbitals to change the electronic feature. The molecular orbital approach is the change on
electronic charges, evidenced from the investigation of three volatile inhalation anesthetics, and
also on molecular conformation, as studied concerning acetylcholine, regarding bond lengths and
angles including torsional angles. These interpretations are carried out by computational methods
concerning the structure-activity relationship.
3. Approach with molecular connectivity: This is based on the structural features of a molecule.
All steric and electronic parameters vary according to their configuration. These include
cyclization, unsaturation, presence of heteroatom, skeletal branching, and position in molecules
with the aid of numerical indices and the series of functional attachments.
4. Approach of linear free energy: The linear free energy approach was based on the selection of
physiochemical parameters of a molecule with a specific biological activity. However, the
biological activity may vary in the physiochemical properties of the drug or molecule and does not
provide prompt success, but it may reveal some beneficial features regarding the molecule.

Concept of drug design and discovery

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NSCBIP/Sem-VI/Medicinal Chemistry III/ Introduction to Drug Design & QSAR /Mr. Samiran Sadhukhan/2024

Quantitative Structure Activity Relationship

Introduction
• Structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR)
study, collectively referred to as (Q)SAR, are theoretical models that can be used to predict the
physicochemical, biological, and environmental fate properties of molecules.
• The aim of QSAR techniques is to develop correlations between biological or pharmacological
activity and physicochemical properties of a set of molecules, in particular, substituent
properties.
• The enormous range of physicochemical properties can be broadly classified into three general
types such as electronic, steric, and hydrophobic property of biologically active molecules.
• The relationship or function is usually (but not always) a mathematical expression derived by
statistical and related techniques, for example, multiple linear regression (MLR). The
parameters describing physicochemical properties are used as independent variables, and the
biological activities are dependent variables.
• Usage of such data may be possible with neural networks to deduce essential data for biological
activities and then using them for prediction. For testing a model for validity, some data are used
to generate a relationship (the training set), while another set of data is reserved as a test set on
which predictions using the rule are made. The entire technique used to derive functional
relationships between the data is collectively known as chemometrics.
Reasons for Carrying Out SAR
• To synthesize a new compound with more specific activity.
• To improve the biological activity of the lead compound.
• To improve the potency and therapeutic index of the new compound as well as the lead
compound.
• To reduce the adverse reaction, toxicity, and other disadvantages associated with the lead
compound as well as the new compound.
• To find any new possible biological activity for the lead compound.
Methods for Performing SAR
• Systemic modification
(a) Homologation and chain branching
(b) Ring chain transformation
(c) Introduction of C≡C and C=C
• Topological analogues
• Synthesis of structural analogues of synthetic chemicals with interesting biological activity.
• Synthesis of novel compounds based on the known structures of naturally occurring biologically
active substances of plant and animal origin.
• Specific design of a drug to interact with receptor site.
Parameters Governing QSAR
The most commonly used parameters are electronic, steric, and parameters related to solubility.
I. Electronic parameters:
a) Hammett constant
b) Taft's substituent constant
c) Inductive substituent constant
II. Steric parameters:
a) Taft's steric substituent constant
b) Molecular connectivity

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NSCBIP/Sem-VI/Medicinal Chemistry III/ Introduction to Drug Design & QSAR /Mr. Samiran Sadhukhan/2024

c) van der Waals dimension

d) Parachor
e) Minimal steric difference
f) Sterimol parameters
III. Partition coefficients:
a) Hansch substituent constant
b) Fragmentation constant
c) Chromatographic Rm value
IV. Biological relationships
a) Hansch analysis
b) Free-Wilson analysis
I. Electronic parameters
a) Hammet constants:
In 1940, Hammett introduced substituent constant that predicted equilibrium and rate constants for
chemical reactions. According to this if an electron-withdrawing group is attached to the aromatic
ring of benzoic acid, it would increase the acid strength.
Hammet substituent constant is expressed as follows:
𝜎𝑥 = log⁡(𝐾𝑥 /𝐾𝑜 )
where
𝜎𝑥 = Hammett constant
𝐾𝑥 = Benzoic acid substituted by the group ‘x’
𝐾𝑜 = Dissociation constant of benzoic acid
The 𝜎 can be expressed by the following equation:
𝜎𝑥 = p𝐾0𝑎 − ⁡p𝐾𝑥𝑎 ⁡
The pKa, value of benzoic acid is 4.19, and p-toluic acid is 4.36 (x = p-CH3). The change in acid
strength brought about by the -CH, group is equal to, 4.19-4.36=0.17. The limitation of this constant
can only be used for nuclear aromatic substituents and their effects on side chain groups in 'm' (or)
'p' position.
b) Taft’s substituent constants:
It is used to measure the polar effects of substituents in aliphatic compounds when the group does
not form a part of a conjugated system. It is defined by the following equation:
σ* = (1/2.48) [log (K/K0)B-log (K/K0)A]
where
σ* = Taft's substituent constant
K = Rate constants for the hydrolysis of the substituted compound
K0= Rate constants for the hydrolysis of the methyl derivative
A = Acid hydrolysis
B = Base hydrolysis
II. Steric parameters
a) Taft’s steric substituent constant
This constant is used to determine the acid hydrolysis, and it is defined by the following equation.
Es = log(K/K0)A
where
Es = Taft's steric substituent constant
K = Rate constants for the hydrolysis of the substituted compound
Ko = Rate constants for the hydrolysis of the methyl derivative
A = Acid hydrolysis

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NSCBIP/Sem-VI/Medicinal Chemistry III/ Introduction to Drug Design & QSAR /Mr. Samiran Sadhukhan/2024

Es values are used to determine the effects of substituents 'x' on the antihistaminic activities of some
analogues.
b) van der Waals dimensions:
van der Waals volume (Vw) and van der Waals radius (rv) explain the actual dimensions of the
group. Since chemical groups are rarely symmetrical, the r v depends on the axis along which it is
measured.
There are three types of radius, namely minimum radius r v (min), similar radius rv ||, and maximum
radius rv (max).
van der Waals radius is defined as the distance of the group protruding from the bulk of the parent
molecule. It can be correlated with biological results in the same ways as Taft's steric substituent
constant.
III. Partition coefficients
a) Hansch substituent constants:
Most of the work in QSAR is based on 1-octanol-water system. Based on this system, Hansch
substituent constants have been explained. It is defined by the following equation:
π = log(PX / PH)

where
π = Hansch substituent constant
PX = Partition coefficient of substituted group ‘x’
PH = Partition coefficient of unsubstituted compound

'x' values can be used to calculate 1-octanol-water partition coefficients. The relation between the
partition coefficient in one solvent system (P1) and those in another solvent system (P2) is shown
by the following equation:
log P1 =K1log P2 + K2
where
K1 and K2= Constants
P1 and P2= Partition coefficients in two different solvent systems
b) Fragmentation constants:
Hansch substituent constant can only be used in certain circumstances. For example, the values for
methyl and methylenic groups are the same in the Hansch scheme. For this condition, the
fragmentation constants are used as an alternative method for calculating 1-octanol-water partition
coefficients. It is defined by the following equation:
log P = Σ af
where
P = Partition coefficient
a = Number of times the group occurs
f = Hydrophobic fragmentation of various groups in the molecule
IV. Biological relationships
a) Hansch analysis:
The systems with which Ferguson's approach was successful (e.g. general anaesthetics) were those
in which equilibrium was quickly established.
According to Hansch analysis, two stages were postulated in drug action.

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NSCBIP/Sem-VI/Medicinal Chemistry III/ Introduction to Drug Design & QSAR /Mr. Samiran Sadhukhan/2024

Stage 1: A random walk from the point of drug administration into the site of action. This will
involve passage over a series of membranes, and it is therefore related to partition coefficient. It is
expressed as f(P), a function of partition coefficient

Stage 2: Attachment to the receptor site and it is expressed mathematically as K X, which depends
on the shape of the molecule and electron density on the attachment groups.

Biological activity (Rb) will be dependent on concentration 'C' and the relationship between those
as follows:
Rb = f(P) KX C
where
Rb = Biological activity
f(P) = Function of the partition coefficient
KX = Attachment to the receptor site
C = Concentration
The Hammett's relationship utilizes electronic properties as the descriptors of their chemical
structure. Sometimes difficulties were encountered when investigators attempted to apply
Hammett-type relationships to biological systems. To overcome this problem, Hansch et al. entered
the scenario with numerical information on lipophilicity, electronic, and steric effects on the model
development. The general form of Hansch equation is as follows:

log BA = a log p + b σ + cEs + 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.
b) Free-Wilson analysis:
It is also known as the additivity model or de novo approach. This method is based on the
assumption that the introduction of a particular substituent at a particular molecular position always
contributes in the same way to the biological potency of the whole molecule, as expressed by the
equation:
log BA = contribution of unsubstituted parent compound + contribution of corresponding
substituents
log ΒΑ = μ + Σ ai aj
where
ai = number of positions at which substitution occurs
aj = number of substituents at that position
μ = overall average

The equation is solved by MLR using the presence (1) or absence (0) of the different substituents
as independent parameters, while the measured activity serves as dependent variable.