
Structure-based drug design:



The macromolecular target can be isolated and
crystallized…then the structure will be determined
using X-ray crystallography.
This structure will not give information about the
binding site.
The co-crystal structure (structure of protein with
the inhibitor inside) is better (WHY?):
 Where is the active site.
 The distance between inhibitor and binding site
boundaries
 The possible bonds between inhibitor and binding site




First the inhibitor will be removed from the
active site (in-silico).
The enzyme structure will be minimized to get
the lowest energy state.
Then lead compounds will be inserted
(docked) into the active site to see how they fit.
Best fit compounds will be synthesized and
tested for activity.

You will have three options:

Use recombinant DNA technology to produce the
enzyme using bacterial cell.

Use the homologue of this enzyme from other
organism such as bacteria or parasite.

Use Ligand Based Drug Design.




Here the crystal structure of the target enzyme
or receptor is not available.
But their ligands are well defined and
characterized.
A pharmacophore will be generated for this
group of ligands.
Compounds from available chemical databases
will be docked on this pharmacophore to find
best analogues of ligands.
Pharmacophore
H-bonding donor
Hydrophobic
H-bonding acceptor
H-bonding acceptor

Involves the design of a novel drug structure
based on a knowledge of the binding site alone.



In this approach, you must have good supply of
enzyme.
Sometimes the bacterial version of enzyme will be
used (obtained by recombinant DNA technology).
The major drawback of this, is the bacterial version is
not identical to the human enzyme…. But it can be
considered very similar.

Steric hindrance and electronic stabilization
have been used to stabilize labile drugs.
Two bulky methyl groups sterically shield the carbonyl group from being attacked
By a nucleophile.
The amide group is electronically more stable than ester group

An other example is isoxazolyl penicillins:
Isoxazole ring is a bulky group which makes oxacillin β-lactamase stable.
Also it is an electron withdrawing group which stabilize the compound
towards acid degradation

Is groups or substituents that normally added
to the drug structure to impair its
metabolism…result in prolonged duration of
action.
Stable towards oxidation at this site

They are stable drugs that under certain
conditions will spontaneously degraded … this
degradation does not depend on the activity of
metabolic enzymes.


An inactive drug which is only converted to
the active form by external stimuli such as
light, heat,…
Example: anticancer porphyrin drugs… large
compound that will pass through the leaky
membrane into the tumor cells… then the site
of tumor will be exposed to red-laser beam to
activate the drug…form a reactive oxygen
radicals that will attack DNA and membranes


An other drug is co-administered with the
principal drug to guard or assist it.
Examples:



Clavulanic acid + Amoxicillin.
Kaletra (combination of Ritonavir and Lopinavir):
Ritonavir is a potent CYP450 inhibitors as well as a
good antiviral agent…prevent Lopinavir oxidation.
The combination of Carbidopa and Levodopa.