Selected topics in drug design

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

How to use co-crystal structure in drug design

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.

If you do not have the crystal structure of your target enzyme 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.

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

H-bonding acceptor

Hydrophobic

H-bonding acceptor

De-novo Drug Design

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.

Steri-electronic modification

Steric hindrance and electronic stabilization have been used to stabilize labile drugs.

O

O

N

H2N

Procaineshort acting anaesthetic

HN N

O

Longer acting anaesthetic

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

Stereoelectronic modification

An other example is isoxazolyl penicillins:

N

S

O

HN

O

OHO

ON

Oxacillin

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

Metabolic blockers

Is groups or substituents that normally added to the drug structure to impair its metabolism…result in prolonged duration of action.

HO

O

O

O

Megesterol acetate

Stable towards oxidation at this site

Self-destruct drugs They are stable drugs that under certain

conditions will spontaneously degraded … this degradation does not depend on the activity of metabolic enzymes.

N O O

O O

NH

O

O

O

O

O

O O

OItracurium

short acting muscle relaxant

Base

H

N

O

O

O

O

Inactive

Sleeping drugs

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

Sentry Drugs

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.