Fundamentals of Rational Design

BY-URAEL G. ([Link], MSc in Medicinal Chemistry) January, 2025

Bule Hora, Ethiopia
 Chapter Outlines
 Structure-Activity Relationships

 Quantitative Structure-Activity Relationships

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 Introduction
Structure-Activity Relationships (SAR)

 Basically, activity of a drug either increases or decreases as a result of some

structure change (relative to the prototype).

 A structure-Activity relationship (SAR) is a statement of the effect of structure

change on biological activity within a congeneric series (a family) of compounds.

 With the structure change known and the biological activity that accompanies this
change, the medicinal chemist can use the information to discover the optimum
drug.

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 How SAR is carried out?
 Developing large number of analogues in a particular chemical category
(Ex. Quinoline, Pyrazole, etc.) by changing different substituents at different
positions.
 Testing them for a particular biological activity, Ex. Anti-diabetic, Anti-
hypertensive, etc
 Analyzing which groups are
 Essential / non-essential
 Increase / decrease / abolish the activity

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 QSAR in drug design
 QSAR aim to relate biological activity of series of cpds to their physicochemical
parameters in quantitative fashion using a mathematical formula.
 These equations may be used by the medicinal chemist to make a more informed
choice as to which analogues to prepare.
 The main properties of a drug that appear to influence its activity are its,
lipophilicity, the electronic effects within the molecule and the size and shape of
the molecule (steric effects).

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 Lipophilicity is a measure of a drug’s solubility in lipid [Link] is usually an
important factor in determining how easily a drug passes through lipid membranes.
 The electronic effects of the groups within the molecule will affect its electron
distribution, which in turn has a direct bearing on how easily and permanently the molecule
binds to its target molecule.
 Drug size and shape will determine whether the drug molecule is able to get close
enough to its target site in order to bind to that site.
 The parameters commonly used to represent these properties are partition coefficients for
lipohilicity, Hammetts constants for electronic effects and TaftMs steric constants for
steric effects.

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 QSAR derived equations take the general form:

 In which the activity is normally expressed as log[1/(concentration term)], usually

C, the minimum concentration required to cause a defined biological response.
1. Lipophilicity
 Two parameters are commonly used to represent lipophilicity, namely the
partition coefficient (P) and the lipophilicity substituent constant (p).
 The former parameter refers to the whole molecule whilst the latter is related
to substituent groups.

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1. Partition coefficient (P)
 Organic medium/aqueous system partition coefficients are the parameters to use as a
measure of the ease of movement of the drug through the membranes.
 The n-octanol–water system is frequently chosen because it appears to be a good mimic
of lipid polarity and has an extensive database.
 The relationship between P and drug activity for a wide range of p values is given by

Where k1, k2 and k3 are constants that are normally determined by regression analysis.

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1.2 Lipophilic substituent constants (p)
 Lipophilic substituent constants are also known as hydrophobic substituent
constants.
 They represent the contribution that a group makes to the partition coefficient and
were defined by Hansch and co-workers by the equation:

 Where PH and PX are the partition coefficients of the standard compound and its
substituted derivative respectively.
 However, when several substituents are present, the value of p for the compound
is the sum of the p values of each of the separate substituent’s.
 The value of p for a specific substituent will vary with the structural
environment of the substituent.

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 A positive p value indicates that a substituent has a higher lipophilicity than
hydrogen and so will probably increase the concentration of the compound in the
n-octanol layer and by inference its concentration in the lipid material of biological
systems.
 Conversely, a negative p value shows that the substituent has a lower lipophilicity
than hydrogen and so probably increases the concentration of the compound in the
aqueous media of biological systems.
 Lipophilic constants are frequently used when dealing with a series of analogues
in which only the substituents are different.

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 As an example, consider the log P values for benzene log P = 2.13),
 chlorobenzene (logP = 2.84) and benzamide (logP = 0.64).
 Having obtained these values, it is now possible to calculate the theoretical
logP value for meta-chlorobenzamide:
 Since benzene is the parent compound, the substituent constants for Cl
and CONH2 are 0.71 and -1.49 respectively.

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2. Electronic effects
 The distribution of the electrons in a drug molecule has a considerable influence on
the distribution and activity of a drug.
 The first attempt to quantify electronic effects of groups on physicochemical
properties of compounds was made by Hammett.
The Hammett constant (σ)
 The distribution of electrons within a molecule depends on the nature of the
electron withdrawing and donating groups found in that structure.
 Hammett used this concept to calculate what are now known as Hammett constants
(σx) for a variety of monosubstituted benzoic acids.

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 Where KH and KX are the equilibrium constants for benzoic acid and
monosubstituted benzoic acids respectively.
 Its value varies depending on whether the substituent is an overall
electron donor or acceptor.
 A negative value for σX indicates that the substituent is acting as an
electron donor group since KH > KX.
 Conversely, a positive value for σX shows that the substituent is
acting as an electron withdrawing group as KH < KX

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3. Steric effects
 The first parameter used to show the relationship between the shape and size
(bulk) of a drug, the dimensions of its target site and the drug’s activity was the
Taft steric parameter (Es).
 It was followed by Charton’s steric parameter (n), Verloop’s steric parameters and
the molar refractivity (MR) amongst others.
The Taft steric parameter (Es )
 Taft (1956) used the relative rate constants of the acid catalyzed hydrolysis of a-
substituted methyl ethanoates to define his steric parameter because it had been
shown that the rates of these hydrolyses were almost entirely dependent on steric
factors.

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 He used methyl ethanoate as his standard and defined Es as:

 Where k is the rate constant of the appropriate hydrolysis and the value of Es=0
when X = H.

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Hansch analysis
 Hansch analysis attempts to mathematically relate drug activity to measurable
chemical properties.
 It is based on Hansch’s proposal that drug action could be divided into two stages:

1. The transport of the drug to its site of action.

2. The binding of the drug to the target site.
 Hansch postulated that the biological activity of a drug could be related to these
parameters by simple mathematical relationships based on the general format:

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 Where C is the minimum concentration required to cause a specific

biological response and k1, k2, k3 and k4 are numerical constants obtained
by feeding the values of the parameters selected by the investigating team
into a suitable computer statistical package.

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Lipinski's rule of five
 Lipinski's rule of five (RO5) is a rule of thumb to evaluate drug likeness or
determine if a chemical compound with a certain pharmacological or biological
activity has properties that would make it a likely orally active drug in humans.
 The rule is important to keep in mind during drug discovery when a
pharmacologically active lead structure is optimized step-wise to increase the
activity and selectivity of the compound as well as to insure drug-like
physicochemical properties are maintained as described by Lipinski's rule.
 Candidate drugs that conform to the RO5 tend to have lower attrition rates during
clinical trials and hence have an increased chance of reaching the market.
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Lipinski's rule states that, in general, an orally active drug has no more than one
violation of the following criteria:
 MW < 500
 Fewer than five H-bond donating functions (nitrogen or oxygen atoms with one or
more hydrogen atoms)
 Fewer than 10 H-bond accepting functions (nitrogen or oxygen atoms)
 Calculated logP (ClogP) between –1 and +5

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