Lecture 1 - Chemical Bonds and Drug Discovery

Question 1

What occurs during Phase I of clinical trials?

Answer 1

First time tested in humans
Uses healthy male volunteers
Identify adverse reactions, safety, pharmacokinetics and pharmacodynamics

Question 2

What occurs during Phase II of clinical trials?

Answer 2

Uses several hundred volunteers

Determines clinical effectiveness and optimum dose

Question 3

What occurs during Phase III of clinical trials?

Answer 3

Uses several thousand volunteers

Determines effectiveness of drug compared to gold standard treatment

Question 4

What occurs during Phase IV of clinical trials?

Answer 4

Continuous monitoring of drug after release
Identification of rare side effects
Drug can be recalled if needed

Question 5

What is selective toxicity?

Answer 5

The drug must kill only the target cells and cause no harm to the healthy cells

Question 6

Name the 8 types of chemical bonds/interactions

Answer 6

Covalent bond
Electrostatic/Ionic bond
Hydrogen bond
Van der Waals interactions
Dipole-dipole interactions
Ion-dipole interactions
Ion-induced dipole interactions
Hydrophobic interactions

Question 7

Describe the covalent bond and give an example of when it occurs

Answer 7

Shared pair of electrons
Quite strong, long lasting
Typical of ‘irreversibly’ binding ligands
E.g. the disulfide bond between two thiol (SH) groups of two cysteine residues

Question 8

Describe the features of non-covalent bonds

Answer 8

Reversible
Drug-receptor interactions are most commonly non-covalent
Occurs at many sites at once

Question 9

Describe the electrostatic/ionic bond and give an example of when it occurs

Answer 9

Electrostatic attraction between two oppositely charged ions
Strength inversely proportional to distance between the ions
Usually responsible for initial interaction as drug docks to target
E.g. between NH3+ and COO-

Question 10

Describe the hydrogen bond and give an example of when it occurs

Answer 10

Forms between a donor (e deficient H atom - usually covalently bonded to an electronegative heteroatom) and an acceptor (electron rich heteroatom - usually O or N with lone pair)
One is weak but cumulatively they are strong
E.g. found between DNA bases

Question 11

How do hydrogen bonds differ from normal ionic bonds?

Answer 11

The orbital on the hydrogen bond acceptor (1p) interacts with the orbitals involved in the covalent bond between the hydrogen bond donor and it’s electronegative heteroatom

Question 12

What is the name of the bond formed in hydrogen bonding and what is the bond angle?

Answer 12

Sigma bond

180 degrees

Question 13

Describe Van der Waals forces

Answer 13

Occurs between two hydrophobic regions
A transient dipole occurs in one molecule due to uneven distribution of electrons
Induces dipole in neighbouring molecule
Individually weak but many can form over large protein surface area

Question 14

Describe dipole-dipole interactions

Answer 14

A PERMANENT dipole arises in a functional group in the drug (such as C=O)
Aligns in parallel with a local dipole moment in the binding site

Question 15

Describe ion-dipole interactions

Answer 15

A PERMANENT dipole arises in a functional group in the drug (such as C=O)
Aligns in parallel with an oppositely charged ion in the binding site
Stronger than dipole-dipole interactions because a full charge is involved

Question 16

What is an ion-induced dipole interaction

Answer 16

An ion induces a dipole within a non-polar molecule

Question 17

Describe hydrophobic interactions

Answer 17

Drug and target are both solvated. If the desolvation energy is greater than the stabilisation energy gained through binding, the drug will be ineffective.
Hydrophobic regions cannot be solvated - water molecules form ordered structure. When two hydrophobic surfaces interact, the surrounding ordered molecules become ‘freed’ and there is a gain in entropy and binding energy

Question 18

What factors influence which diseases pharmaceutical companies choose to develop treatments for?

Answer 18

Economic - is the government rich enough to pay, is the disease very prevalent
Medical - treat the most severe diseases

Question 19

What is an orphan disease?

Answer 19

Rare diseases not normally focussed on by pharmaceutical companies as they are unlikely to make much profit from them
The government will put economic incentives in place to facilitate development of orphan drugs i.e. protocol assistance

Question 20

What factors should be considered when choosing a drug target?

Answer 20

What is the target (RICE, nucleic acid)
Is the drug an agonist, antagonist, inverse agonist
Does the drug need selectivity between species i.e. penicillin targets cell wall synthesis, human cells don’t have walls
Does the drug need selectivity between targets i.e. antipsychotics would have less side effects if they were selective for D2 rather than D2 and D3

Question 21

What are the desirable features of a bioassay?

Answer 21

High throughput screening (HTS)
Validity - reliable and clear cut
Cheap
Sensitive and selective - no false positives or false negatives

Question 22

Name two types of bioassay

Answer 22

Radioligand binding assay - tells you how well a ligand binds to a receptor by measuring radioactivity before and after attempt to displace
Functional assay - radioactive GTP (GTP-gamma-S) binds irreversibly to Galpha subunit. Tells you how activated a GPCR is

Question 23

Name 10 sources of drug discovery and name an example for each

Answer 23

Plant kingdom - Opioids
Microbiological world - Penicillin
Marine world - Acyclovir 
Animal kingdom - Epibatidine (analgesic)
Venoms & toxins - Captopril (ACE inhibitor)
Medical folklore - Dantron (laxative)
Natural ligands - AZT, thymidine analogue
Existing drugs - Captopril --> Enalapril
Computer aided design
Serendipity - Viagra

Question 24

What determines the strength of a hydrogen bond?

Answer 24

How electronegative the atom bonded to the H atom is

How electronegative the bond acceptor is

Question 25

Give an example of an ion-induced dipole interaction

Answer 25

The cation-pi interaction
A cation (e.g. positive quarternary ammonium ion) interacts with an electron rich region (e.g. aromatic ring). The charge on the ion distorts the pi electron cloud to induce a dipole moment. The ring moves to stabilise the positive charge 
Utilised by acetylcholine