Pharmaceutical Industry

Lecture 3
Interaction of Drug to its Receptor

• Many drugs exert their physiological effects by binding to a specific cellular

binding site called a receptor.

• Drugs that recognise the binding site

(receptor) is called molecular
recognition.
• A drug interacts with its receptor by
- hydrogen bonding,
- electrostatic attractions, and
- van der Waals interactions

• Drug receptors are often glycoproteins or lipoproteins. Some receptors are part of
cell membranes, while others are found in the cytoplasm—the material outside the
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nucleus.
• Drugs have considerable specific binding site.

• Example 1: Epinephrine has intense effects on cardiac muscle, but no effect on

muscle in other parts of the body.

• The greater the affinity of a drug for its binding site (receptor), the higher is the
drug’s potential biological activity.

• Example 2: Nucleic acids—particularly DNA—also act as receptors for certain

kinds of drugs.

• Chloroquine (an antimalarial) and 3,6-diaminoacridine (an antibacterial) are flat

cyclic compounds. They can slide into the DNA double helix between base pairs
and interfere with the normal replication of DNA.

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Example 3:
• When excess histamine is produced by the body, it causes the symptoms
associated with the allergic responses.

• This is due to the result of the protonated ethylamino group anchoring the
histamine molecule to a negatively charged portion of the histamine
receptor.

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• Drugs that interfere with the natural action of histamine — called
antihistamines—bind to the histamine receptor but do not trigger the same
response as histamine.

• Like histamine, these drugs have a protonated amino group that binds to the
receptor.

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 Drugs as Enzyme Inhibitors

• Penicillin, for example, destroys bacteria by inhibiting the enzyme that

synthesizes bacterial cell walls.

• Bacteria develop resistance to penicillin by secreting penicillinase, an enzyme

that destroys penicillin by hydrolyzing its -lactam ring before the drug can interfere
with bacterial cell wall synthesis.

OH H

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• Chemists have developed drugs that inhibit penicillinase. If such a drug is given
to a patient along with penicillin, the antibiotic is not destroyed. This is an example
of a drug that has no therapeutic effect itself, but acts by protecting a therapeutic
drug.

• One of the penicillinase inhibitors is a sulfone, which is easily prepared from

penicillin by oxidizing the sulfur atom with a peroxyacid.

• Because the sulfone looks like the original antibiotic, penicillinase accepts it as
a substrate and inactivates penicillinase, thereby wiping out the resistance to
penicillin.

• Administering penicillin and the sulfone in combination results in drug synergism:

The sulfone inhibits the penicillinase, so penicillin won’t be destroyed and will
be able to inhibit the enzyme that synthesizes bacterial cell walls. 6
 Quantitative Structure–Activity Relationships (QSAR)

• The enormous cost involved in synthesizing and testing thousands of modified

compounds in order to find an active drug.

• Therefore scientists develop a more rational approach—called rational drug design

(without using animal model).

• Rational drug design is based on the design of organic small molecules that are
complementary in shape to the biomolecular target such as protein. After
binding of organic molecules to its target, it will activate or inhibit the function
of a target.

•As a result it will give a therapeutic benefit to

the patient.

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• The physical property of a drug cannot take the place in vivo testing.

• The technique of relating a property of a series of compounds to biological activity

is known as a quantitative structure–activity relationship (QSAR).
(i.e: relationship between chemical structures and biological activity)

• In QSAR modeling, the predictors consist of physico-chemical properties of

chemicals; the QSAR response-variable could be a biological activity of the
chemicals.

• QSAR models first summarize a supposed relationship between chemical

structures and biological activity in a data-set of chemicals. Second, QSAR
models predict the activities of new chemicals. In this way molecular modified
compounds without the desired activity can be avoided.

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 Combinatorial Organic Synthesis

• Large collections of organic compounds are required to screen for biological activity
in order to find the new drugs. Therefore, organic chemists need synthetic strategy
for the mass production.

• This strategy is called combinatorial organic synthesis which involves the

synthesis of a large group of related compounds - known as a library - by
covalently connecting sets of building blocks of various structures.

• For example, if a compound can be synthesized by connecting three different

building blocks, and if each set of building blocks contains 10 interchangeable
compounds, then 1000 (10x10x10) different compounds can be prepared.

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• Currently, organic chemists create libraries of small organic molecules for use in a
combinatorial approach for modifying lead compounds or as a complement to
rational drug design.

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 High-throughput screening (HTS)
• High-throughput screening (HTS) is a method for scientific experimentation
especially used in drug discovery in the fields of biology and chemistry.

• A researcher can conduct millions of chemical, genetic, or pharmacological tests

quickly using high-throughput screening.

• High-throughput screenings use robotics, data processing/control software,

liquid handling devices, and sensitive detectors.

• Through this process one can rapidly identify active compounds, antibodies, or
genes that modulate a particular biomolecular pathway.

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• An example of the approach used in combinatorial synthesis is the creation of a
library of benzodiazepines.

• These compounds can be originating from three different sets of building blocks: a
substituted 2-aminobenzophenone, an amino acid, and an alkylating agent.

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• The 2-aminobenzophenone is attached to a solid support.

• The amino acid—N-protected and activated by being converted into an acyl

fluoride—is then added.

• After the amide is formed, the protecting group is removed and the seven-
membered ring is created as a result of imine formation.

nucleophile

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• A base is added to remove the amide hydrogen. The final product is then removed
from the solid support.

- HX

• In order to synthesize a library of these compounds, the solid support containing

the 2-aminobenzophenone can be divided into several portions, and a different
amino acid can then be added to each portion.

• Each ring-closed product can also be divided into several portions, and a different
alkylating agent can be added to each portion.

• In this way, many different benzodiazepines can be prepared. 14

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