Structure activity relationship in
Dr Suyash Bharat
PG JR 1ST PHARMACOLOGY, GMC Haldwani (Nanital)
Structure activity relationship (SAR).
• The analysis of the dependence of biological
effects of a chemical upon its molecular
• Molecular structure and biological activity are
correlated by observing the results of
systematic structural modification on defined
• SAR is the relationship between the
chemical or 3D structure of a molecule and
its biological activity.
• Determination of the chemical groups
responsible for evoking a target biological
effect in the organism.
• Quantitative SARs (QSAR)as a special case of
SARs (when relationships become quantified)
• Attempts to find consistent relationship
between the variations in the values of
molecular properties & the biological activities
for a series of compounds so that these
“rules” can be used to evaluate new chemical
• 3D QSAR –most powerful technique available
for analog – based drug design.
History- Brown and Fraser in 1869
• They showed that many compounds
containing tertiary amine groups became
muscle relaxants when converted to
quaternary ammonium compounds.
• This hypothesis was later rejected.
• Ing states “Molecules that block the effects of
natural neurotransmitters (antagonists)
generally are larger in size than the native
• Both agonists and antagonists share common
• Composition and arrangement of chemical
functional groups, determines the type of
pharmacologic effect ,it possesses.
Selectivity of Drug Action and Drug
• Similar molecules exert similar biological
actions in a qualitative sense.
PHYSICOCHEMICAL PROPERTIES OF
• Acid-Base Properties
• Water Solubility of Drugs
• Electronic parameters
• Possible to predict ,if a molecule gets
ionized or unionized at a given pH simply by
knowing if the functional groups on the
molecule are acidic or basic.
• Quantitatively predict the degree of ionization
of a molecule.
• Henderson-Hassalbach equation
Water Solubility of Drugs
• It Greatly affects the routes of administration.
• Two key concepts :
• 1) hydrogen bond forming(Drugs with
possibility of more hydrogen bond formation
will have more solubility)
• 2) ionization of functional groups.
OAldehyde / ketone
Ion - dipole bonds
Acidic form of amines
Basic form of carboxylic acid
Predicting Water Solubility: Empiric
• Based on carbon- solubilising potential of
several organic functional groups.
• Solubilising potential of the functional groups
exceeds the total number of carbon atoms
present, then the molecule is considered to be
water soluble. Otherwise, its water insoluble.
• Functional groups that can interact either
through intramolecular hydrogen or ion-ion
interactions will decrease the solubilizing
potential of each group.
Intramoleculare interact. reduce water sol.
Strong intramolec interact.
Predicting Water Solubility: Analytical
• PARTITION CO-EFFICIENT- It is the extent of distribution
of drug between oil phase and water phase.
• If the drug is more hydrophobic it will have high p
value and it can cross biological membranes easily.
• Partition co-effecient of a drug can be determined by
its distribution in an octanol-water mixture.
P= Concentration of drug in octanol
Concentration of drug in aqueous solution
Log P =Σπ(fragments)
• Log of the partition coefficient for a
molecule Predicts Water Solubility
• Log P is the sum of the hydrophobic and
hydriophilic characteristics of the organic
functional groups making up the structure of
• Thus, logP is a measure of the solubility
characteristics of the entire molecule.
STEREOCHEMISTRY AND DRUG
• Stereo isomers are compounds containing the
same number and kinds of atoms, the same
arrangement of bonds, but different three-
• 2 types enantiomers and diastereoisomers
• If functional groups are in the proper 3D
orientation, the drug can produce a very strong
interaction with its receptor.
• The physiochemical properties of a drug molecule
dependent on (a) functional groups in the
molecule (b)spatial arrangement of these groups.
• Enantiomers when introduced into an
Asymmetric environment(human body) ,it will
display different physiochemical properties,
producing significant differences in their
pharmacokinetic and pharmacodynamic
Easson and Stedman Hypothesis
• reasoned that differences in biological activity
between enantiomers resulted from selective
reactivity of one enantiomer with its receptor.
• They postulated that such interactions
require a minimum of a three-point fit to the
receptor. (incerase potency of enantiomers)
Conformational Isomerism and
• dynamic process
• Isomerization takes place via rotation about
one or more single bonds.
• Neurotransmitter acetylcholine
demonstrates the concept of
• Rotation around the central Cα-Cβ bond
produces the greatest spatial rearrangement
• When the ester and trimethylammonium
group are 180° apart, the molecule is said to
be in the anti or staggered conformation.
• maximum separation of the functional
• Rotation of one end of the Cα-Cβ bond by
120° or 240° results in the two gauche , or
• Gauche conformation is the form that binds to
the nicotinic receptor
• Anti form, (achiral) binds to the muscarinic
pruning(refinement of lead structure)
Pharmacophore (its a spatial arrangement of functional
groups essential for biological activity)
Determination of the Pharmacophore
• The pharmacophore of a drug molecule is that
portion of the molecule containing the
essential organic functional groups that
directly interact with the receptor active site
• Pharmacophore may constitute a small
portion of the molecule.(very specific)
• Example narcotic analgesic morphine.
Alterations in Alkyl Chains: Chain
Length, Branching, and Rings
• Simply changing the length of an alkyl chain by
one CH2 unit or branching the chain may alter its
lipophilic character properties of absorption,
distribution, and excretion alter.
• Alkyl chain is directly involved in the receptor
interaction alter the binding characteristics.
• Conformational become less flexible affect
spatial relationship of functional groups
influence receptor binding
FUNCTIONAL GROUP MODIFICATION.
ISOSTERISM AND BIOISOSTERISM
• Modify the compound to reduce or eliminate
undesirable features without losing the
desired biological activity.
• Done by Replacement or modification of
functional groups with other groups having
similar properties is known as "isosteric
replacement" or "bioisosteric replacement"
Langmuir in 1919 defined the concept
• "Comolecules are thus isosteric if they
contain the same number and arrangement
of electrons. The comolecules of isosteres
must, therefore, contain the same number of
atoms. The essential differences between
isosteres are confined to the charges on the
nuclei of the constituent atoms."
• Describe the similarities in physical properties
among atoms, functional groups, radicals, and
• Hinsberg applied the concept of isomerism to
entire molecules developed the concept of
• The groups that can be exchanged for one
another in aromatic ring systems without
drastic changes in physicochemical properties
relative to the parent structure.
• Eg -Benzene, thiophene, and pyridine
• "Bioisostercs are compounds or groups that
possess near equal molecular shapes and
volumes, approximately the same distribution
of electrons, and which exhibit similar physical
properties such as hydrophobicity.
• Bioisosteric compounds affect the same
biochemically associated systems as agonist or
antagonists and thereby produce biological
properties that are related to each other."
• Nonclassical bioisosteres are replacements of
functional groups not defined by classical
• Thou they mimic spatial arrangements ,
electronic properties, or some other
physiochemical property of the molecule or
functional group critical for biological activity.
• eg -use of a double bond to position essential
functional groups into a particular spatial
configuration critical for activity.
• The trans isomer of diethylstilbestrol has
approximately the same potency as estradiol,
whereas the cis isomer is only one-fourteenth
FUNCTIONAL GROUP MODIFICATION.
• Bioisosterism include the replacement of the
initial molecular scaffold by a different one,
keeping the same biological activity called
• Eg- diazepam, zolpidem, zaleplon , and zopiclone
which exert the same biological response acting
as full agonists of GABA-A (g-aminobutyric acid)
receptor at the benzodiazepine site though being
• Examples illustrated that similar biological
activity can be obtained with structurally
different molecules which seems to contradict
the bioisosterism principle discussed.
• Charge – sum of partial charge
• F charge- sum of formal charge
• Apol -sum of atomic polarizability
• Dipole – dipole movement
• HOMO-highest occupied molecular orbital energy
• LUMO- lowest unoccupied molecular orbital
• Sr – superdelocalizability.
• Medicinal Chemistry I -IInd Module, Drug
• Essentials of drug designing . V kothekar 1st
• SAR applicability domain -Nina Nikolova and