Most often, subtle changes occur in the side
chain and main chain positions of the enzyme in order to
bind the substrates transition state optimally.
(Pauling).
http://pubs.acs.org/doi/full/10.1021/bi050247e
James G. Robertson*
Softzymics, Inc., Princeton, New Jersey 08540
Biochemistry, 2005, 44 (15), pp 5561–5571
DOI: 10.1021/bi050247e
Publication Date (Web): March 22, 2005
Some interesting paragraphs from the paper ...
Thus, it should be stated again. Enzymes are catalysts,
and the catalytic event is at least as important if not more
important than the binding event. Enzyme catalysis progresses
through binding events, conformational changes, one or more
transition states, or reaction intermediates, and product
release, and all of these steps occur with defined rate
constants. The rate constants define a thermodynamic profile
that can be used for drug design, and this differentiates
enzymes from all other target classes.
the larger the increase in replication time, the more toxic the drug
In
addition, purely kinetic information can be used to predict
potential drug toxicity. As an example, a detailed pre-steady-
state kinetic analysis of human mitochondrial DNA poly-
merase has been used to predict the potential toxicity of
marketed antiviral drugs.
One
of the major lessons to be learned from marketed drugs is
that nature has designed enzymes to perform a selective
chemical reaction, and therefore, it is likely that the most
potent drugs to be discovered or designed will be related to
the substrate structure, reactivity, or electrostatic potential
surface of intermediate(s) or transition state(s).
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