Medicinal Chemistry Chapter Questions Flashcards
1.1.1- The hormone adrenaline interacts with proteins located on the surface of cells and does not cross the cell membrane. However, larger steroid molecules such as estrone cross cell membranes and interact with proteins located in the cell nucleus. Why is a large steroid molecule able to cross the cell membrane when a smaller molecule such as adrenaline cannot?
The ability of a molecule to cross the fatty cell membrane has little to do with its size, but more with its hydrophobic character.
Estrone is more hydrophobic than adrenaline since it has a larger carbon skeleton and only two polar functional groups. Thus, the molecule is hydrophobic in character and can dissolve through the fatty cell membrane.
Adrenaline has four polar functional groups and a much smaller carbon skeleton. Thus the polar functional groups dominate in determining the character of the molecule making it very polar and unlikely to pass through the cell membrane.
1.1.2- Valinomycin is an antibiotic which is able to transport ions across cell membranes and disrupt the ionic balance of the cell. Find out the structure of valinomycin and explain why it is able to carry out this task.
outside is hydrophobic and inside is hydrophilic. as a result, it can easily pass through the cell membrane and encapsulate polar ions;
1.1.3- Archea are microorganisms that can survive in extreme environments, such as high temperatures, low pH, or high salt concentrations. It is observed that the cell membrane phospholipids in these organisms are markedly different from those in eukaryotic membranes. What differences are present and what function might they serve?
The alkyl chains are linked to the glycerol skeleton by ether linkages rather than by ester linkages. Ethers are chemically more stable than esters to extreme conditions.
The long alkyl chains are also branched, unlike those in eukaryotic cell membranes. Branching makes the chains more resistant to oxidation.
1.1.4- Teicoplanin is an antibiotic which ‘caps’ the building blocks used in the construction of the bacterial cell wall such that cannot be linked up. The call wall barrier surrounding the bacterial cell membrane and the building blocks are anchored to the outside of this cell membrane prior to their incorporation into the cell wall. Teicoplanin contains a very long alkyl substituent which plays no role in the capping mechanism. However, if this substituent is absent, activity drops. What role do you think this alkyl substituent may serve?
The alkyl group is hydrophobic and is embedded into the cell membrane. As a result, the drug is anchored to the cell membrane and is located on its outer surface such that it is ideally located to interfere with cell wall synthesis.
1.1.5- The Ras protein is an important protein in signaling processes within the cell. It exists freely in the cell cytoplasm, but must become anchored to the inner surface of the cell membrane in order to carry out its function. What kind of modification to the protein might take place to allow this to happen?
A hydrophobic chain could be attached to the Ras protein which would serve to anchor it to the inner surface of the cell membrane, in the same way in which teicoplanin is anchored to the outer surface of cell membranes (compare answer 5 above). The actual process by which a hydrophobic chain is attached to the Ras protein is shown below where the chain is attached to a cysteine residue.
1.1.6- Cholesterol is an important constituent of eukaryotic cell membranes and affects the fluidity of the membrane. Consider the structure of cholesterol and suggest how it might be oriented in the membrane.
Cholesterol has one polar group - the alcohol group. This can form an H-bond to the polar head group of phospholipids. The rest of the molecule is hydrophobic and will sink into the cell membrane to form hydrophobic interactions with the alkyl side chains of the phospholipids.
1.1.7- Most unsaturated alkyl chains in phospholipids are cis rather than trans. CompWhat conclusions can you make regarding the packing of such chains in the cell membrane and the effect of the membrane fluidity?
Phospholipids are an amphipathic molecules, therefore they have both hydrophobic and hydrophilic ends. The main components are unsaturated alkyl chains and proteins. The main reason for the dominance of cis over trans is that it increases the fluidity of the cell membrane by adding a kink to the chain. This kink results in the hindrance of the hydrophobic interaction, thereby, increase the fluidity of the cell membrane.
cis-double bonds introduce a kink into the chain which will hinder the regular packing of the hydrophobic chains. This increases the fluidity of the cell membrane.
1.1.8- The relative strength of carbonyl oxygens as hydrogen bond acceptors is carboxylate ion> amide>ketone> ester. Suggest why the order is as shown.
This reflects the fact that the greater the electron density on the carbonyl oxygen, the stronger it will act as a hydrogen bond acceptor.
The carboxylate group is the strongest hydrogen bond acceptor since a full negative charge is shared between both oxygens.
The carbonyl oxygen of the amide will also act as a good hydrogen bond acceptor since the lone pair of electrons on nitrogen can interact with the carbonyl group to increase electron density on the carbonyl oxygen as shown below.
No such interaction occurs for the ketone or ester carbonyl groups, but the carbonyl groups are still polarised resulting in the oxygen having a slightly negative charge. Consequently it can still act as a hydrogen bond acceptor, but less strongly.
1.3.1- Enzymes can be used in organic synthesis. For example, the reduction of an aldehyde is carried out using aldehyde dehydrogenase. Unfortunately, this reaction requires the use of the cofactor NADH, which is expensive and is used up in the reaction. If ethanol is added to the reaction, only catalytic amounts of cofactor are required. Why?
the enzyme- catalysed reduction of an aldehyde requires one equivalent of the cofactor NADH, which is oxidized to NAD+. However, if ethanol is added to the reaction, aldehyde dehydrogenase can catalyse its oxidation to acetaldehyde. int the process , NAD+ is converted back to NADH.
1.3.2- Acetylcholine is the substrate for the enzyme acetylcholinesterase. Suggest what sort of binding interactions could be involved in holding acetylcholine to the active site.
The active site of AChE comprises 2 subsites - the anionic site and the esteratic subsite.
The anionic subsite accommodates the positive quaternary amine of acetylcholine as well as other cationic substrates and inhibitors. The cationic substrates are not bound by a negatively-charged amino acid in the anionic site, but by interaction of 14 aromatic residues that line the gorge leading to the active site.
The esteratic subsite, where acetylcholine is hydrolyzed to acetate and choline, contains the catalytic triad of three amino acids: serine 200, histidine 440, and glutamate 327. The hydrolysis reaction of the carboxyl ester leads to the formation of an acyl-enzyme and free choline. Then, the acyl-enzyme undergoes nucleophilic attack by a water molecule, assisted by the histidine 440 group, liberating acetic acid and regenerating the free enzyme.
1.3.3- The ester bond of acetylcholine is hydrolysed by acetylcholinesterase. Suggest a mechanism by which the enzyme catalyses this reaction.
a mechanism similar to that described for the hydrolysis of peptide bonds by chymotrypsin would be feasible involving a catalytic triad of serine, histidine, and aspartate ( or glutamate). Serine would serve as a nucleophile, histidine as an acid/base catalyst, and aspartate (or glutamate) as an activating and orientating group.
1.3.4- Suggest how binding interactions might make acetylcholine more susceptible to hydrolysis.
in general, binding interactions will involve acetylcholine being bound in a particular conformation such that the binding interactions are maximised. As a result certain bonds might be placed under strain with the result that they are broken more easily.
For example, a hydrogen bond involving the carbonyl oxygen of acetylcholine may result in a weakening of the carbonyl pi bond such that it is more easily broken in the first stage of the enzyme - catalyses mechanism. Note also that the strength of this interaction is likely to be more significant for the transition state compared to the substrate itself. in this way, the transition state will be stabilized more significantly than the substrate resulting in a lowering of the activation energy
1.3.6- Lactate dehydrogenase has 1000-fold selectivity for lactate as a substrate over malate. However, if a mutation occurs that alters an active site glutamine reside to an arginine reside, the enzyme shows a 10,000-fold selectivity for malate over lactate. Explain this astonishing transformation.
The structure of Lactate has a methyl group at one of its ends whereas malate has carboxylate (both the structures have carboxylate at one of the ends). While carboxylate is negatively charged, methyl group is non-polar and uncharged.
The interaction indicates that the amino acid glutamine is present at the active site/allosteric site of the enzyme which is responsible for the binding of the enzyme to the substrate. While glutamine has an uncharged side chain, arginine has a positively charged group on its side chain. Therefore, the negatively charged malate can form strong interaction with the positively charged arginine. This explains the altered behavior of the enzyme when glutamine is replaced by arginine.
//In the unmutated version of lactate dehydrogenase there is a glutamine residue in the active site which contains a neutral primary amide group at the end of the side chain. In the mutated version of the enzyme, this amino acid has been replaced by an arginine residue which contains a protonated guanidinium functional group. This can form an additional ionic interaction with malate that is not possible with lactate. The additional binding interaction accounts for the selectivity for malate over lactate as the former will have a much stronger affinity for the active site.
2.7.1- It is known that the amino acid at position 523 of the cyclooxygenase enzyme is part of the active site. In the isoenzyme COX-1, this amino acid is isoleucine, whereas in COX-2, it is valine. Suggest how such information could be used in the design of drugs that selectively inhibit COX-2.
isoleucine has a larger side chian that valine and so there is less space available in that region of the active site for COX-1 than there is in the corresponding region in COX-2. Drugs can be designed that take advantage of this difference such that they fit into the active site of COX-2 but not the active site of COX-1
2.7.2- Neostigmine is an inhibitor of acetylcholinesterase. The enzyme attempts to catalyze the same reaction on neostigmine as it does with acetylcholine. However, a stable intermediate is formed which prevents completion of the process and which results in a molecule being covalently linked to the active site. Identify the stable intermediate and explain why it is stable.
The reaction catalysed by acetylcholinesterase on acetylcholine is the hydrolysis of the ester to produce acetic acid and choline. With neostigmine, a stable complex with the enzyme is formed. Following the mechanism through, serine acts as a nucleophile and a nucleophilic substitution reaction takes place on the urethane with loss of the phenol group. However, once this has occurred, serine is ‘capped’ with a stable urethane group which is resistant to hydrolysis.
