Transcript Drug discovery 4

Structure-Activity-Relationships (SAR’s)
• Once a lead has been discovered, it is important to
understand precisely which structural features are
responsible for its biological activity (i.e. to identify
the “pharmacophore”)
The pharmacophore is the precise section of the
molecule that is responsible for biological activity
• This may enable one to prepare a more active molecule
• This may allow the elimination of “excessive” functionality, thus
reducing the toxicity and cost of production of the active material
• This can be done through synthetic modifications
• Example: R-OH can be converted to R-OCH3 to see if O-H is
involved in an important interaction
• Example: R-NH2 can be converted to R-NH-COR’ to see if
interaction with positive charge on protonated amine is an
important interaction
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Next step: Improve
Pharmacokinetic Properties
• Improve pharmacokinetic properties.
pharmacokinetic = The study of absorption,
distribution, metabolism and excretion of a drug
(ADME).
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Metabolism of Drugs
• The body regards drugs
as foreign substances,
not produced naturally.
• Sometimes such
substances are referred
to as “xenobiotics”
•Body has “goal” of removing such xenobiotics
from system by excretion in the urine
•The kidney is set up to allow polar substances
to escape in the urine, so the body tries to
chemically transform the drugs into more polar
structures.
Metabolism of Drugs (cont.)
• Phase 1 Metabolism involves the
conversion of nonpolar bonds (eg C-H
bonds) to more polar bonds (eg C-OH
bonds).
• A key enzyme is the cytochrome P450
system, which catalyzes this reaction:
RH + O2 + 2H+ + 2e– → ROH + H2O
Mechanism of Cytochrome
P450