 Structure-based drug design:  The macromolecular target can be isolated and crystallized…then the structure will be determined using X-ray crystallography.

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Presentation transcript:

 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 H-bonding acceptor Hydrophobic 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.