Structure – Activity Relationships:

In SAR, the part of the molecule important for biological activity is found. Molecular modeling and
X ray crystallography can be used to identify important binding interactions. Various chemical functional
groups present in the structure that can bind to the drug’s target, or assist and protect the drug on its journey
through the body. Recognizing functional groups and intermolecular bonds they can form is important in
understanding how a molecule can bind to its target.

(A) Binding role of alcohols and phenols:

Alcohols and phenols are often involved in hydrogen bonding. The oxygen can act as a hydrogen
bond receptor and hydrogen can act as a hydrogen bond donor. One or more interactions may be important
in binding the drug to the binding site. This can be tested using a methyl ether or ester analogue. There are
two reasons why the ether might hinder or prevent hydrogen bonding of the original alcohol or phenol. The
obvious explanation is that the proton of the original hydroxyl group is involved as a hydrogen bond donor
and if it is removed, the hydrogen bond is lost. The extra bulk of methyl group hinder the close approach and
hydrogen bonding is weakened. The ester analogue can not act as a hydrogen bond donor either. The extra
bulk of acyl group is even greater than the methyl group in the ether. Both phenols and alcohols can be
converted to ethers and esters to see the effect of hydroxyl functional group on the binding. In case of
phenols, hydroxyl group is linked to aromatic ring. It is important to know the role of aromatic ring in the
intermolecular interactions.

(B) Binding role of aromatic ring:

Aromatic rings are planar, hydrophobic structures, commonly involved in van der Waals and hydrophobic
interactions with flat hydrophobic region of binding site. An analogue containing a cyclohexane ring in
place of the aromatic ring is less likely to bind so well, as the ring is not flat. The axial protons can interact
weakly, but serve as buffers to keep the rest of the cyclohexane ring at a distance. Hence the methods of
converting aromatic rings to cyclohexane rings are less likely to be successful with most lead compounds.

(C) Binding role of double bonds:

Similar to aromatic rings, alkenes with double bond are also planar and hydrophobic, so they can also
interact with hydrophobic region of binding site through van der Waal and hydrophobic interaction. The
activity of equivalent saturated structure is worth testing. The saturated alkyl groups are bulkier and can not
approach the relevant region of the binding site so closely. Alkenes are easier to reduce than aromatic rings,
so it may be possible to prepare the saturated analogue directly from the lead compound.

(D) Binding role of ketones:

A ketone group is planar and can interact with binding site through hydrogen bonding where the carbonyl
oxygen acts as a hydrogen bond acceptor. Two such interactions are possible, as two lone pairs of electrons
are available on the carbonyl oxygen. The carbonyl group also has a significant dipole moment and hence
dipole-dipole interaction with binding site is also possible. It is easy to reduce ketone to alcohol, but the
geometry changes from planar to tetrahedral. Such alteration may weaken the hydrogen bonding and dipole
interaction.

(E) Binding role of amines:

Amines can be involved in hydrogen bonding as hydrogen bond donor or hydrogen bond acceptor. The
nitrogen has lone pair of electrons and can act as hydrogen bond acceptor. Primary and secondary amines
have N-H group and can act as donor. Aromatic amines can act only as donor, because lone pair interacts
with the aromatic ring. Amines may be protonated when it interacts with its target binding site, which means
it is ionized and can not act as a hydrogen bond acceptor. But it can act as hydrogen bond donor with
relatively stronger bond. To test whether ionic or hydrogen bonding interactions are taking place, an amide
analogue can be studied. Amide group prevents (i) nitrogen as a hydrogen bond acceptor (ii) protonation of
nitrogen and rules out possibility of ionic interaction.
(F) Binding role of amides:
Amides are likely to interact through hydrogen bonding. The carbonyl group oxygen atom can act as a
hydrogen bond receptor and has potential to form two hydrogen bonds. Amide group prevents (i) nitrogen as
a hydrogen bond acceptor (ii) protonation of nitrogen and rules out possibility of ionic interaction. Amide
group is planar and can not rotate due to partial double bond character. Suitable analogues for amides are
secondary and tertiary amines, ketones etc.