SAR and QSAR

SAR & QSAR
SAR & QSAR

• SAR (structure activity relationship)
• The analysis of the dependence of biological effects of a chemical upon its
molecular structure.
• Molecular structure and biological activity are correlated by observing the results
of systematic structural modification on defined biological endpoints.
• QSAR (Quantitative structure activity relationship)
• A QSAR is a mathematical relationship between a biological activity of a
molecular system and its geometric and chemical characteristics.
SAR
SAR is a qualitative not a quantitative relationship
Aim
• Identify which functional groups are important for binding and/or activity
Method
1. Alter, remove or mask a functional group
2. Test the analogue for activity
3. Modifications may disrupt binding by electronic / steric effects
4. Easiest analogues make from lead compound
5. Possible modifications may depend on other groups present
6. Some analogues may have to be made by a full synthesis (e.g. replacing an aromatic ring with a cyclohexane
ring)
7. Allows identification of important groups involved in binding
Structure Activity Relationships
• Compounds with similar structures to a pharmacologically active drug are often
themselves biologically active.
• This activity may be either similar to that of the original compound but different
in potency and unwanted side effects or completely different to that exhibited by
the original compound.
• These structurally related activities are commonly referred to as

structure–activity relationships (SARS).
• A study of the structure–activity relationships of a lead compound and its
analogues may be used to determine the parts of the structure of the lead
compound that are responsible for both its beneficial biological activity, that is, its
pharmacophore, and also its unwanted side effects.
• This information may be used to develop a new drug that has increased activity, a
different activity from an existing drug and fewer unwanted side effects.
• Structure–activity relationships are usually determined by making minor changes
to the structure of a lead to produce analogues and assessing the effect these
structural changes have on biological activity.
• The investigation of numerous lead compounds and their analogues has made it
possible to make some broad generalizations about the biological effects of
specific types of structural change.
These changes may be conveniently classified as changing:
1. The size and shape of the carbon skeleton
2. The nature and degree of substitution
3. The stereochemistry of the lead
• The selection of the changes required to produce analogues of a particular lead is
made by considering the activities of compounds with similar structures and also
the possible chemistry and biochemistry of the intended analogue.
• Structural changes that result in analogues with increased lipid character may
exhibit either increased activity because of better membrane penetration (n = 3-6)
or reduced activity because of a reduction in their water solubility.
• However, whatever the change, its effect on
• Water Solubility,
• Transport Through Membranes,
• Receptor Binding,
• Metabolism
• Pharmacokinetic Properties Of The Analogue
• Furthermore, changing the structure of the lead compound could result in an
analogue that is too big to fit its intended target site.
• Computer assisted molecular modeling can alleviate this problem, provided that
the structure of the target is known or can be simulated with some degree of
accuracy.
CHANGING SIZE &
SHAPE
Changing Size & Shape
• The shapes and sizes of molecules can be modified in a variety of ways, such as
changing the number of methylene groups in chains and rings, increasing or
decreasing the degree of unsaturation and introducing or removing a ring system
(Table 4.1).
• These types of structural change usually result in analogues that exhibit either a
different potency or a different type of activity to the lead.
NEW SUBSTITUENTS
New Substituents
• The new substituents may either occupy a previously unsubstituted position in
the lead compound or replace an existing substituent.
• Each new substituent will impart its own characteristic chemical, pharmacokinetic
and pharmacodynamic properties to the analogue.
• Generalize about some of the changes caused by the introduction of a particular
group into a structure (see Table 4.2).
• The choice of substituent will ultimately depend on the properties that the
development team decide to enhance in an attempt to meet their objectives.
• Practical results of such a structural change will often be different from the
theoretical predictions.
• The incorporation of any group will always result in analogues with a different
size and shape to the lead compound.
• Introduction of a chiral center, which will result in the formation of stereoisomers,
which may or may not have different pharmacological activities.
• Alternatively, it may impose conformation restrictions on some of the bonds in
the analogue.
Bioavailability of Drugs
• The introduction of a new group may result in an increased rate of metabolism, a
reduction in the rate of metabolism or an alternative route for metabolism.
• These changes could also change the duration of action and the nature of any side
effects.
• Mono- and diortho-methylation with respect to the phenolic hydroxy group of
paracetamol produces analogues with reduced hepatotoxicity (liver toxicity). It is
believed that this reduction is due to the methyl groups preventing metabolic
hydroxylation of these ortho positions.
• The position of substitution is critical. In one position the new group will lead to
an enhancement of activity, while in another position it will result in a reduction of
activity.
• For example, the antihypertensive clonidine with its o,o’-dichloro substitution is
more potent than its m,p-dichloro analogue (ADHD, injection vs. oral).
Replacing Groups
• Analogues formed by replacing an existing group by a new group may exhibit the
general stereochemical and metabolic changes.
• The choice of group will depend on the objectives of the design team. It is often
made using the concept of isosteres (groups that exhibit similarities in their
chemical and/or physical properties).
Replacing Groups
Replacing Groups
• Isosteres exhibit similar pharmacokinetic and pharmacodynamic properties.
• The replacement of a substituent by its isostere is more likely to result in the
formation of an analogue with the same type of activity as the lead than the
totally random selection of an alternative substituent
QSAR
QSAR
• It is said to be a mathematical relationship in the form of an equation between the
biological activity and measurable physiochemical parameters.
• QSAR attempts to identify and quantify the physicochemical properties of a drug
and to see whether any of these property has an effect on the drugs biological
activity
• The parameters used in QSAR is a measure of the potential contribution of its
group to a particular property of the parent drug.
• Activity is expressed as log (1/C).

• C is the minimum concentration required to cause a defined biological response.
• Physicochemical property as log p.
QSAR (types)
• 2D analysis
• Hansch analysis
• Free-Wilson Analysis
• 3D analysis
• Comparative Molecular Field Analysis (CoMFA)
• Steric values
• Electrostatic values
• Comparative Molecular Similarity Index Analysis (CoMSIA)
• It provide steric and electrostatic values and consider
• H - bond donor
• H - bond acceptor
• Hydrophobic field
SAR &QSAR
HANSCH ANALYSIS
• Electronic properties (substitutions on aromatics system para & meta
only)
• Lipophilicity (Log P)
• Steric effect (bulkiness of compounds)
FREE-WILSON ANALYSIS
• Substitution at specific position (compare potency of parent and
analogs)
MIXED APPROACH
• Follow above rules

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SAR & QSAR

SAR & QSAR

• These structurally related activities are commonly referred to as

• Activity is expressed as log (1/C).

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