Pharmaceutical Industry

Lecture 4

Classical Discovery and Development of Drugs

• The first step of drug discovery is connected to the health problem that needs a
cure.

• Next is to find a chemical substance that shows promising activity against the
target disease.

• In classical drug discovery, TWO sources of possible new drugs are “Natural
Products and Chemical compounds that were synthesized for this purpose”.

• Normally they are results of long-term observation of nature.

• The next step is design of the suitable screening model because it is not
possible to use human patients for screening of unknown substances.

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• The model can be a cell culture (eg. bacteria) or a laboratory animal (eg. a
mouse) in which the disease is artificially induced.

• These compounds are tested on the models and those that show a positive
effect are selected as hits and the others are shelved for possible later use.

• Second test confirmation is required for confirmation and also investigate the
substance has no deleterious toxic effects on mammals. A confirmation hit is
called a ‘lead’.

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• If a good lead is found, it is chemically modified until the efficacy is optimal
and the unwanted effects are minimal.

• After drug discovery, the next is preclinical phase whereby the routine of
synthesis, the safety and the general properties of drug substance are
established.

• This is a prerequisite before it can enter the clinical phase, which is testing
on humans.

• The tentative conclusion of the development process is granting of

marketing authorization by the competent authorities of the countries in which
the drug is to be sold.

• Even after a drug is in the market, research continues to improve its dosage
forms or to discover new applications.

• It is tested whether the drug substances is also suited to treat other diseases.

• Sometimes, adverse side effects are observed that need investigation. 3

• The lead compound serves as a model for further development. Similar
substances are synthesized and compared to the lead.

• The chemical structure is elucidated and carefully analyzed to determine which

part of the molecule is responsible for the pharmacological effect. It is called
pharmacophor.

• The original lead compound can be modified to change its physical and
physiological properties, but the pharmacophore remains the same.

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Modern drug discovery

• Today pharmaceutical companies apply computerized robotic systems in drug

discovery.

• The starting point is the chemical library. This library does not contain books, but
chemicals.

• Many companies keep small samples of all chemical compounds that they ever
synthesized or extracted from the plant material.

• The amount of the samples is usually small and they are kept in microplates in
dedicated temperature-controlled storage facilities.

• Chemical libraries of large pharmaceutical companies contain several million

different compounds.

• The size of the library is increased continuously using high throughput

synthesis.
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• The concept of combinatorial chemistry is applied.

• It means that available analogues of starting material A are combined with

analogues of B.

• This leads to a very large number of reactions requiring handling by robotic

systems. Let us assume there are three analogues of A (Al, A2, and A3) and
three analogues of B (Bl, B2, and B3); then the following combinations are
possible:
Al + Bl => Xl, Al + B2 => X2, Al + B3 => X3
A2 + Bl => X4, A2 + B2 => X5, A2 + B3 => X6
A3 + Bl => X7, A3 + B2 => X8, A3 + B3 => X9

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• This example illustrates that the combinatorial approach yields a large number of
different products.

• The combinatorial library can be based on structure-activity relationship (SAR).

SAR can be used to select starting compounds with chemical structures that
are known to have pharmacological activity.

• On the other side, it can also help to avoid structures that have negative effects,
such as high toxicity, low bioavailability, or slow metabolism.

• To have a large library a high throughput technique is used for screening (high
throughput screening [HTS]).

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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.

• These experiments provide starting points for drug design and for understanding
the interaction or role of a particular biochemical process in biology.

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• Binding assays and microplate robotic techniques are used for HTS.

• When the physiological target is identified, a receptor binding assay is

developed which should be a characteristic indicator of the intended biological
effect.

• Then all or selected substances from the library are screened with the assay.

• Very small amounts of the substances are transferred to plastic plates that have tiny
holes, keeping the reagents for the assay.

• A plate can have 96, 384, or several thousand wells. This means screening takes
place on a micro liter scale with unbelievable high speed, many thousand substances
per day.
Conventional techniques are precluded,
because they are too slow and insufficient
substance is available for testing on
animals.

Basic setup of a high

throughput binding assay 9
Virtual screening (VS) is a computational
technique used in drug discovery to search
libraries of small molecules in order to
identify those structures which are most
likely to bind to a drug target, typically
a protein receptor or enzyme.

A new molecular entity (NME) is a

drug that contains an active moiety that
has never been approved by the FDA or
marketed in the US
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