Question

Question 6 The following three molecules are camptothecin analogues that target the topoisomerase I enzyme and are used to treat cancer. LOH Oy “ HO a. Using common structural features generate a simple ligand-based pharmacophore to explain why these compounds may be binding to the same enzyme. List how can pharmacophores be used in a research setting to aid drug discovery? b. ehte c. Given that the compound 3 is metabolised by an esterase in vivo (compounds 1 and 2 are not metabolised by esterases). what additional pharmacophoric point might you suggest?

Answer 1

a)

Structure of Camptothecin:

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As you can see, this is the structure of Camptothecin. Now, look at the three molecules. It is clearly visible that the three molecules are structurally modified versions of camptothecin. This common structure of camptothecin is present in all three molecules. Thus these molecules can be considered as structural analogs of camptothecin. So these molecules can compete with camptothecin and can bind to the topoisomerase I.

b)

A pharmacophore can be defined as the molecular features that must possessed by a ligand to interact with a biological molecule, in order to activate a response.

This is very important in drug discovery. By looking at the pharmacophore of a particular molecule, we can understand what all features must be present in the structure of the drug that we design. We can design new structural analogs for the molecules and thereby inhibit several biochemical pathways.

c)

Esterase is an enzyme that cleaves an ester bond. In molecule 3, there is an ester bond. So this bond will be cleaved to get a new molecule. However, sometimes this may affect the pharmacophore of the drug molecule. One of the molecules that we get will still be a structural analog of camptothecin. But still, the efficiency will be questionable.

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