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SUCCESS STORIES
Influences on change in approaches
to substance design and innovation
The goals that Envision Chemistry seeks
to achieve are not new. There are several sources of pressure
that give rise to the chemical industry wanting to innovate
in respect of 'HS and E' acceptability, and some of these
are very old indeed. They include:
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Concern for worker
safety |
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Concern for safety of the population
and the environment close to a facility |
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Unacceptable side effects, e.g.
non-biodegradable surfactants gave rise to excessive
amounts of foam in water - replacements were soon
developed. DDT was found to be having significant
effects up the food chain - now pesticides are thousands
of times more active than DDT and not persistent |
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Changing performance criteria,
for example, engine manufacturers have set lubricant
specifications that are a consequence of environmental
and performance considerations |
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Wider regulation, such as limiting
the use of volatile organic substances, requiring
the need for water-based systems to be developed.
Replacement of heavy-metal based technologies (e.g.
corrosion inhibitors, paint and plastics additives,
lead in fuel) by new approaches based on organic systems |
…not forgetting basic competitive
advantage even where no regulation applies, leading to
more efficient science-based solutions to particular needs.
The fundamental tools in today's
design-lead chemistry are:
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Chemical property prediction |
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Molecular modelling |
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Multivariate statistical analysis |
In respect of environment and health
considerations, these are coupled with a quantitative
understanding of hazard and risk to allow companies to
innovate further. Design approaches have been used strongly
in pharmaceutical and agrochemical research, and are used
in other areas too.
Successes of Computer Aided Drug
and Agrochemical Design
Computer aided chemical design (CADD)
began to be adopted in the pharmaceutical and agrochemical
industries in the late 1970’s - early 1980’s.
In the last 25 years these techniques have become so widely
accepted that every research based company of a reasonable
size in these industries has a dedicated CADD group. The
earliest success stories involved a method known as Quantitative
Structure-Activity Relationships (QSAR) in which mathematical
models are constructed between a biological response and
a quantitative description of chemical structure. Fujita
(1) reported at a conference in 1984 the optimization
of the herbicidal lead structure shown below:
The activity of analogues of this compound
could be related to hydrophobicity and size by the following
equation:
Another CADD technique
which complements QSAR is Structure Based Drug Design
(SBDD) which makes use of the X-ray structure of biological
targets such as enzymes and pharmacological receptors.
A recent article on the impact of structure guided drug
design (2) lists over 40 compounds discovered with the
aid of SBDD which have entered clinical trials. At the
time of writing of that article (August 2003) seven of
the compounds had become approved and marketed drugs.
Perhaps the most dramatic
illustration of the success of SBDD is seen in this graph
from the Centre for Disease Control
(copied with thanks from www.nigms.nih.gov/news/facts/structure_drugs.html)
AIDS deaths dropped sharply in 1995,
when HIV protease inhibitors became available to patients.
1 : T. Fujita, in: QSAR and Strategies
in the Design of Bioactive Compounds, J. K. Seydel, Ed.,
VCH, Weinheim, 1985, pp 207-218.
2 : L.W. Hardy & L. Milikayil,
Curr. Drug Discovery, December 2003, pp 15-20.
Photography courtesy of Keran McKenzie
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