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Many currently used drugs were discovered through the traditional pharmaceutical screening of substances
isolated from natural sources. Natural sources, usually plants, marine organisms and micro-organisms, are
a fantastic reservoir of molecules, and many of them remain to be screened for their potential pharmaceutical
properties. Some substances correspond to chemicals isolated from natural sources used in folk medicine. The
activity of these natural compounds can also be improved by chemical modification of the natural structure.
It can happen that the natural source of a powerful and effective drug is not able to provide the active
component in sufficient quantity to satisfy medical needs. In such a case it is necessary to have recourse
to an efficient chemical synthesis. For instance, the chemical compound Taxol is very active against ovarian
and breast cancers, but the molecule is isolated only in very small amounts from the bark of Taxus baccata
(yew tree). However, the active molecule obtained from the bark is actually an assembly of two components,
the main part of which can also be obtained in significant amounts from yew tree pine needles. Combination
of this naturally-produced material with the minor component, obtained by direct chemical synthesis,
constitutes Taxol virtually identical to that obtained from the bark. During the laboratory synthesis
procedure, an intermediate, TaxotereTM, is obtained which is even more active than Taxol itself.
Traditional screening approaches to drug discovery have low success rates (averaging no more than one
success in over 20,000 products screened). Combinatorial chemistry has recently revolutionised drug
discovery by providing access to a huge number of molecules. This new technique can be applied to small
molecules as well as macromolecules such as proteins, nucleotides and carbohydrates. Large numbers of
substances can now be screened for a specific drug activity in new automated screening systems that utilise
the natural structures which are relevant for diseases. These receptors, enzymes, channels, etc can be
obtained in useful quantities using gene technology. Such speed will have considerable impact on the
efficiency of drug research and discovery processes.
Molecular modelling and simulation methods, rational design and computational studies of protein-drug
interactions (lock-and-key chemistry) permit an insight into how drugs work at the atomic and molecular
levels and significantly aid the design of active molecules. The mechanisms which determine the recognition
behaviour and operation of drugs towards proteins can be studied in detail, the computer making it possible
for the scientists to see what shape and charge distribution the guest molecule should have to fit into the
binding niche of the respective protein host. This means that the usual trial-and-error strategy, or random
search, can be improved upon by means of computational methods.
Once a molecule is identified as a candidate drug, chemists and chemical engineers have to find the best way
to synthesise it. Selective synthesis, which gives only the desired product and avoids the formation of
undesirable by-products, is a permanent challenge for chemists. Stereo-selectivity, and in particular
asymmetric synthesis, is a key area due to its potential for the production of single enantiomers
(mirror image molecules). This is particularly important in the case of bio-active compounds since
often only one of the enantiomers shows the desired activity. Two of the major approaches in this area are
the use of transition metal catalysts bearing chiral ligands and the application of bio-transformations
where enzymes themselves are employed as the enantio-selective catalyst. Use of catalytic antibodies is
also a growing area of activity.
Chemists, together with biochemists, have contributed to remarkable advances in many aspects of health and
life sciences. The synthesis and industrial production of highly complex molecular structures like steroidal
hormones and their analogues to provide contraceptive agents have had an impact not only on medicine but also
on society. Chemical synthesis of peptides and small proteins is now a routine automated technique and could
provide peptides in useful quantities. Some important physiological peptides for clinical use, for example
peptidal hormones, are now produced by such methods. DNA and RNA fragments are now available via automated
chemical synthesis. In particular, synthetic oligonucleotides of the 'antisense' type (having the
complementary sequence of a genetic message) can bind selectively to the corresponding sequence of DNA or
RNA with high specificity. Treatments of some diseases, ranging from virus infections to genetic disorders,
now rely upon molecules found by these techniques. Oligosaccharides, which are associated with group blood
factors, have applications in blood diagnosis and are made by direct chemical synthesis.
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