(a) (5 marks) Give the precise full name of the type of calcium channel that is a target for anti-hypertensive

drugs. Describe briefly the role of this protein in controlling blood pressure.

L-type calcium channels. There are 3 types: Cav1.2a which is found in the heart, Cav1.2b which is found in smooth muscles and Cav1.2c which is distributed on other tissues. L-type calcium channels consists off 5 subunits. The subunit is the one that controls the entry of calcium into the cell. CEBs usually interact with this subunit. The entrance of Calcium into the cell through L-type calcium channels cause vasoconstriction. So, CEBs decrease blood pressure by closing these channels.
(b) (9 marks) Define, in less than 100 words each, the terms vasorelaxant, pharmacophore and virtual screening as they are used in this paper. You may need to look beyond the paper to find sufficient information.

Vasorelaxant: any substance that causes dilation of blood vessels. Pharmacophore: the functional groups of any drug that interact with the target protein inside the body. Those functional groups interact with the binding site of the drug.

Virtual screening: the use of computer applications to predict whether a specific compound can be a lead compound. Usually, they can predict the physiological effects of the drug from its structure.

(3 marks) Explain briefly in molecular terms why only one of four possible stereoisomers of the drug diltiazem is used in therapy.

Only the cis(+) form of dilitazem is used in treatment. Dilitazem has 3 chiral centers at C-2 and C-4. The cis(-) enantiomers has weaker activity. On the other hand, the trans compounds have no vasorelaxant activity. The racemic mixtures has vasoconstrictice effect. AS a result, the cis(+) form of dilitiazem is the only form has has benefits in therapy. Also, the ligand binding site on the subunit is stereoselective.

(e) (4 marks) Explain briefly what the graph in Figure 8 of this paper shows about the mode of binding of the benzenesulfonamide compound 15.

From the graph, we can notice that the percentage of diltiazem bound to the receptor is reduced when it is co-administered with compound 15, this indicates that the binding site for compound 15 and diltizem is the same binding site.

(f) (6 marks) Reproduce the structures of diltiazem and compound 15 using SymexDraw in such a way that the similarities and differences between these compounds are highlighted. Label the regions of these molecules that are likely to bind to the calcium channel in similar ways Hydroxyl group on the phenyl ring of dlitiazem may bind to the same residue as that of chlorine atom of compound 15. Oxygen substituted at C-3 of the benzothiazepine ring may bind to the same residue as that of sulfonyl in compound 15. Dialkylamino group in diltiazem and the piperidine in compound 15 may interact with the binding site in similar pattern

OH

O S N

N
S O N O O

Compound 15

Diltiazem