BMP: Drug targets (carbohydrates)

Question 1

What are primary, secondary, tertiary and quaternary amines?

Answer 1

CH₃-NH₂

(CH₃)₂NH

(CH₃)₃N

(CH₃)₄N⁺

Question 2

What is a quaternary Amine also known as?

Answer 2

Catinoic salt

Question 3

What is the dominant factor determining boiling point?

Which of these bonds are strongest?

Answer 3

Hydrogen bonding

O—-H bonding stronger than N — H binds

Question 4

What are nitrogen containing functional groups?

Answer 4

Question 5

What properties of AA is there?

Answer 5

• Amphoteric - act as acids and bases
• a-carbon chiral centre
  *

Question 6

What AA are:

• Basic
• Acidic
• Hydrophobic
• Aromatic

Answer 6

• Basic
  
  • arginine, histidine, lysine
• Acidic
  
  • aspartic acid, glutamic acid
• Hydrophobic
  
  • alanine, glycine, isoleucine, leucine, proline, valine
• Aromatic
  
  • phenylalanine, tryptophan, tyrosine

Question 7

What are primary, secondary, teritary, quaternary alcohols?

Answer 7

Question 8

Discuss phenol properites

Answer 8

• Phenols are about a million times more acidic than alcohols
• Practical consequence – phenols are soluble in NaOH
• More acidic due to resonance stabilised phenoxide anion

Question 9

What do EWG do to the anion?

Answer 9

•Electron-withdrawing groups stabilise the alkoxide

form by spreading the charge over a larger volume

making the alcohol more acidic.

Question 11

What do carbohydrates play an important role in?

Answer 11

Cell recoginisation, regulation and growth

• Energy storage - glycogen
• Structure - cellulose and starch

Question 12

What does glycomics mean?

Answer 12

The study of carbohydrates/ glycomes as drug targets or drugs themselves

Question 13

What substances is glucose the monomer for?

Answer 13

Glycogen, starch, cellulose

Question 14

What is an example of carbohydrates play in there role of cell regonition, regulation and growth?

Answer 14

Bacteria and viruses are microgorganisms which must recoginize the host cells before infecting them. The carbohydrate molecules/ structures play a role in recoginition. Blocking these recognition sites will hopefully prevent microganisms from recognising them and infecting cells

Question 15

What are examples of glycoconjugates?

Why are these useful?

Answer 15

Glycoproteins and proteoglycans

Rather than just carbohydrates involed in the recoginition process it normally involves glycoproteins instead.

Glycoproteins benefically compared to AA as rather than only 2 sites on the AA avialbe to react (-COOH/NH2) there is multiple -OH groups available for esterifcation reactions on the carbohydrate. This gives rise to greater stuctural diversity

Question 16

What are carbohydrates and lipids known as

Answer 16

GLycolipids

Question 17

What is an antigen?

Answer 17

A substance which when recognized as non-self by the adaptive immune system triggers an immune response where antibodies are produced specififcallt against it to react with it

Question 18

What are antibodies?

Answer 18

Proteins which indentify with forgin cells/macrophages and mark them for destruction. Also can be used to carry specific drug targets

Question 19

What are AB produced by?

Answer 19

B lymphocytes

Question 20

What are the problems with AB?

How is this problem over come?

Answer 20

The body produces Anti-AB to the AB

Using part human, part rat (66% human/ Rat)

Question 21

What are examples of AB that reach the clinic?

Answer 21

Omalizumab - targets imuglobin E and treatment for allergic ahstma

Adalimumab - first fully human AB. USed for rheumatoid arthritis and works by binding to inflam molecule cytokine-TNF-a

Question 22

Describe Reversible competitive inhibiton, include examples

Answer 22

• The inhibitor binds to the active site of the enzyme by intermolecular forces (e.g. H-bond, hydrophobic interactions, Van der Waals) so the inhibition is reversbile
• The drug binds to the active site and then is released and binds again
• As the concentration of the natural substrate increases, the inhibtor competes more effectively with the drug for the active site - making the drug less effective
• Competetive inhibitor - Rosuvastatin
• ethanol can be used as a competitive inhibitor for anti-freeze posioning

Question 23

Describe the irreversible inhibition

Answer 23

• These bind to the active site irreversibly and block the enzyme permanently. This is usually effected by the alkylation of nucleophilic R groups within the active site, e.g. the OH or SH of Serine and cysteine.
• The majority of this type of inhibitor are, by their very nature, highly toxic. There are, however, exceptions e.g. Disulfuram, some proton pump inhibitors and anti-obesity drug Orlistat.

Question 24

• Describe allosteric binding
• What is good about allosteric binding?

Answer 24

• Allosteric binding sites are different sites to the active site. Here agents which control enzyme activity bind
• When the inhibitor binds here it causes the acitve site and allosteric site to change shape. The AS is no longer recogonizable to the substrate molecule, therefore its action is inhibited
• This gives rise to 2 sites for drug targeting

Question 25

What is an example of an allosteric inhibitor? What does it do?

Answer 25

6-mercaptopurine Inhibits the firts enyzme involved in purine synthesis therefore blocks DNA synthesis and leads to cell death

Question 26

Describe non-competivie and uncompetive inhibitors

Answer 26

* Rare * Tend to bind to enzyme-substrate complex as opposed to enzyme itself

Question 27

Describe transition-state analogues and give an example Why are these difficult?

Answer 27

* Renin inhibitors * These bind very potently (strongly) but not irreversbily * They mimic the transition state of the catalysed reaction * difficult because need to know the transition state and hard to mimic

Question 28

What is an example of a group which has optimum properties for a transition-state analogue? What are the properties? What is a benefit of this group?

Answer 28

Hydroxyethylene - has the tetrahedral geometry and two hydorxyl groups required for optimum binding stable to hydrolysis as no leaving group

Question 29

Describe suicide substrates

Answer 29

* Agents that are designed to undergo anenzyme-catalyzed transformation which converts them into a highly reactive species, that binds irreversibly to the active site. * Example – Clavulanic acid. * Once bound undergoes biotransformation which posions the active site

Question 30

Describe isoenzymes and give examples

Answer 30

Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Examples COX-1 and COX-2. This can be exploited for the treatment of rheumatoid arthritis, where COX-2 becomes activated, producing excess inflammatory prostaglandins. Another example is the Monoamine Oxidase inhibitors.

Question 31

give examples of MAOIs

Answer 31

Two isozymes MAO-A and MAO-B. The isozyme MAO-A is selective for noradrenaline and serotonin, whereas MAO-B is selective for dopamine. Clorgiline – antidepressant Selegline and Levodopa – treatment for Parkinsons.

Question 32

bendfits of isoenyzme targeting?

Answer 32

Isozymes – targeting of these could lead to less side effects and more selective and effective drugs.

Question 33

**NUCLEIC ACIDS**

Question 34

What type of DNA binding is there?

Answer 34

**3 reversible modes:** * INTERCALATION – Major drug class * GROOVE BINDING * ELECTROSTATIC **Irreversible:** * ALKYLATING AGENTS – Major drug class

Question 35

Describe intercalation binding What is the stucture of intercalating drugs like?

Answer 35

Intercalating drugs tend to me planar or heteroaromatic (cationic) compounds which slide in between base pair layers of DNA. They can have non-planar cationic or neutral parts to their structure which purdrude into a DNA groove

Question 36

Discuss specifciity in terms of intercalatinf drugs

Answer 36

Display no perefecnes for specific base pair binding or a slight GC prefercne

Question 37

Give an example of an intercalating anti-cancer drug What properties are needed for an anti-tumour drug

Answer 37

1. Actinomycin 2. High levels of intercalating binding needed for anti-tumour activity but not all intercalating binding molecules have AT activity

Question 38

What are examples of intercalation drugs?

Answer 38

1. Chloroquine and quine - antimalarial drugs 2. Aminoacridines (proflavine) - antibacterials 3. Doxorubican - chemotherpay drug

Question 39

What does Doxorubican do?

Answer 39

intercalattion prevents the normal function of topoimsomerases

Question 40

What is topoisomerase?

Answer 40

Enzymes which change the topological state of nucleic acids by disrupting the sugar-phosphate backbone of DNA They are involved in metabolism of DNA and cell division 2 forms topo I and II - both targets for chemotherapeutic innervation

Question 41

Describe the general mechanism for groove bindiing

Answer 41

Involves direct interaction betwen the molecule and the edge of the base pair in wither the major or minor grooves

Question 42

Properties of groove binding drugs

Answer 42

* Positive * Linked rather than fused aromatic or heteroaromatic rings * creasant shape

Question 43

what do the minor and major grooves differ in?

Answer 43

* Electrostatic potential * Hydrogen bonding * hydration * Stearic interferance

Question 44

Examples of groove binding drugs

Answer 44

* bis-imidazoles * Netropsin * distamycin lead compounds with anticancer and antiviral properties Minner groove binders

Question 45

Describe electrostatic binding

Answer 45

* Generally non-specific interactions between cations and anions phosphate groups of DNA exterior backbone * ANy positive molecule can assoicate in this way

Question 46

Descibe alkylating agents Examples

Answer 46

* Highly electrophillic compounds which react with nucleophiles to form strong covalent bonds therefore this binding is irreversbile * nitrogen mustards, nitrosoureas, busulfan, **cisplatin** and mitomycin C.