| The Combinatorial Chemistry Revolution
In many biotech and pharmaceutical companies there is a revolution going on in the way new drugs are discovered.
Using combinatorial chemistry to generate new molecules, in the course of a year a large company may screen a staggering number of molecules for biological activity.
In the early stages of drug discovery, these tests are performed with high-throughput screening (HTS) robotic systems, which measure a candidate molecule's ability
(a) to bind to a target site on an isolated enzyme or protein and cause the macromolecule to cease its undesired action, or (b) to stunt the growth or kill a colony of
pathogenic cells or organisms. As disease-related genes are discovered with accelerating frequency, more opportunities arise to test new drug targets.
A successful hit at the early stage is just the beginning in a long journey before a molecule can become a drug. A miniscule number of molecules succeed in the
end. The Odds of Success
Typically, a large
pharmaceutical company will test over 3,000,000 molecules for activity. About 30,000 "hits" may be discovered in a year. Of these only about 30 candidate molecules
reach development in a year. Of these, about 3 molecules are anticipated to enter the market as drugs, only once in a while as "blockbusters". More often than not,
only one molecule enters the market. |
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KEY POINTS in Drug Discovery
- the majority of pharmaceutical discovery projects aim for an orally available form of a new therapeutic principle
- in vitro assays are used to predict in vivo human absorption
- although biological activity is a key issue in initial screening of drug candidates, there are other factors…
INTESTINAL ABSORPTION
Permeability
Solubility
Retention by membrane
These are not usually part of optimization in early stages of discovery.
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Drugability - Getting The Job Done
Sometimes, quite active compounds are rejected due to poor oral absorption pharmacokinetics: they work in a test
tube, but in the body they just can’t reach their target sites. For example, the molecule may be just too insoluble in water, and like "brick dust" is eliminated before
it has a chance to do anything. To get to a site of therapeutic action, a molecule has to traverse many barriers formed by cell membranes, composed of
phospholipid bilayers, which are oily barriers that block the passage of charged or hydrophilic molecules. Even if a molecule easy dissolves, if it is highly
charged, it will not pass the oily barriers. Other effects, such as metabolism and efflux will limit absorption.
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The Need for Better Prediction
At the start, many candidate molecules fail because they can’t effectively cross phospholipid bilayer barriers to get into
the circulatory system. Laboratory test animals usually are not employed at the earliest screening stage to assess molecules for absorption efficiency. Often,
cultured cells, such as Caco-2, are used for this purpose, but the tests are costly and require a special license. As a cost-effective partner technique, it is possible
to predict if a molecule will have absorption difficulties by measuring its following physicochemical properties: model-membrane bilayer permeability coefficient,
aqueous solubility and extent of retention by the membrane - hence the acronym PSR (permeability-solubility-retention). For ionizable molecules, the PSR
parameters have measurable dependence on pH. At a given pH, the PSR parameters indicate the charge state of a drug molecule and its solubility in water and
membranes, which predict the chances of the molecule being absorbed in vivo into the circulatory system. Measurements of PSR profiles are used to prioritize
molecules for further studies and to reject some molecules altogether.
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