Biomedical Engineering Reference
In-Depth Information
increased computational power allow researchers to test hundreds of thousands of
compounds against the target to identify those that might have good potential.
Of late, thanks to advances in chemistry and pharmacology, scientists can aban-
don the generally ineffi cient method of systematic screening of existing molecules
for a novel approach known as
rational drug design
. Applying analytical methods
to fi gure out the genesis of the disease from its onset to chronicity, they come up
with prototypes of a drug molecule designed from scratch. The structure of the tar-
get biomolecule can be identifi ed with the assistance of X-ray crystallography or
nuclear magnetic resonance. This information can then be used in computer model-
ing and simulation to predict the characteristics of potential drug candidates so that
they can not only exhibit affi nity and selectivity to the target biomolecule but also
affect its biological and physical properties in the desired way. Designed drug
molecules can be synthesized by researchers once they understand the molecular
characteristics necessary for binding to the biological target. The designed drug
molecules are then tested on the target biomolecule.
Next, scientists must learn how the generated compounds are absorbed into the
bloodstream, if they are distributed to the proper site of action in the body, whether they
can be metabolized effi ciently and effectively, if they are being successfully excreted
from the body, and whether they appear to be toxic in any way. Lead compounds that
survive the initial testing can be optimized further or altered to make them safer and
more effective. By changing the structure of a compound, scientists can change its prop-
erties to make it less likely to interact with other processes and mechanisms in the body,
thus reducing the potential side effects. Hundreds of different variants of the initial leads
are made and tested. Teams of biologists and chemists work closely together: the biolo-
gists test the effects of these variants on biological systems, while the chemists use that
information to make additional alterations that are then retested by the biologists. After
many iterations, the fi nal compound becomes a
drug candidate
.
Even at this early stage, researchers attend to practical issues, considering the
drug formulation (e.g., its right concentration as well as the inactive ingredients that
will hold it together and make it dissolve at the desired rate), the administration
route (e.g., oral application, injection, inhaler), even the details regarding the transi-
tion to large-scale manufacturing. Techniques for making the drug in the lab may
not translate easily to large volume production. Still, before clinical trials can start,
suffi cient quantities of the drug will be needed.
Preclinical testing
. With one or more optimized compounds in hand, researchers
turn their attention to extensive preclinical testing. Before any human subjects can
be involved in the trials, a safe starting dose must be established. Scientists carry
out in vitro and in vivo tests to check the safety profi le, the toxicology and the
effi cacy of the studied compounds.
6
Starting with approximately 5,000-10,000 lead
compounds, scientists winnow them down to between 1 and 5 molecules (candidate
drugs), which then enter a series of clinical trials.
6
In vitro tests are experiments conducted in the lab, usually carried out in test tubes and beakers.
In vivo studies are those in living cell cultures and experimental animals, conducted to gauge the
effects of the drug candidate on the metabolism and the systems of intact living organisms.
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