Medicine: Medicinal Chemistry and the drug development process

Question 1

What is medicinal chemistry?

Answer 1

Medicinal Chemistry is a multidisciplinary science aimed at the design and synthesis of new chemical entities in order to generate new medicines for the diagnosis, prevention and treatment of disease.

Question 2

Name some drug targets

Answer 2

Proteins

				- - Enzymes
				- - Receptors
				- - Transporters
			- Nucleic Acids
			- Carbohydrates
			- Lipids

Question 3

Name some ways leads are discovered or brought up as ideas

Answer 3

• Copying others
• Leads from nature or folk remedies
• Educated guessing
• Combinatorial libraries

Question 4

What is a Pharmacophore?

Answer 4

Identification of the structural elements within a compound that confers beneficial activity; called its Pharmacophore

Question 5

edits to pharmacophore that drug companies do?

Answer 5

Changes to chemical structure that can change activity: Potency, ADME, toxicology
Changing the size and shape of the molecule
New substituents to alter receptor/enzyme binding or changing water solubility
Restriction of conformation
Replacement of functional groups with active mimics, known as bioisosteres.

Question 6

4 types of ways drugs can bind to their target

Answer 6

Electrostatic or Ionic bonds

Hydrogen bonds

Van der Waals interactions

Dipole-dipole, ion-dipole and induced dipole interactions

Question 7

How strong are ionic bonds? In what conditions are they stronger?

Answer 7

Strongest of the intermolecular bonds (20-40 kJ mol-1)
The strength of interaction drops off less rapidly with distance than with other forms of intermolecular interactions

Stronger interactions occur in hydrophobic environments

Question 8

Do hydrogen bonds vary in strength?

Answer 8

Yes

Question 9

Why is an amide N not likely to participate in an ionic or hydrogen bond?

Answer 9

because the

lone pair is delocalized.

Question 10

2 examples of strong hydrogen bond acceptors

Answer 10

carboxylate ion, phosphate ion

Question 11

6 examples of moderate hydrogen bond acceptors

Answer 11

carboxylic acid, amide oxygen, ketone, ester, ether, alcohol

Question 12

6 examples of poor hydrogen bond acceptors

Answer 12

sulfur, fluorine, chlorine, aromatic ring, amide nitrogen, aromatic amine

Question 13

One example of a good hydrogen bond donor

Answer 13

Quaternary ammonium ion

Question 14

Describe the strength of hydrogen bonds in relation to other types of bonds

Answer 14

Weaker than electrostatic interactions but stronger than van der Waals interactions

Question 15

How are hydrogen bonds formed?

Answer 15

A hydrogen bond takes place between an electron deficient hydrogen and an electron rich heteroatom (N or O)
The electron deficient hydrogen is usually attached to a heteroatom (O or N)

Question 16

What is a hydrogen bond acceptor?

Answer 16

The electron rich heteroatom is called a hydrogen bond acceptor

Question 17

what is a hydrogen bond donor?

Answer 17

The electron deficient hydrogen is called a hydrogen bond donor

Question 18

Where do ionic bonds take place?

Answer 18

Takes place between groups of opposite charge

Question 19

Strength of ionic bond in relation to the distance between the two charged groups?

Answer 19

The strength of the ionic interaction is inversely proportional to the distance between the two charged groups

Question 20

Most important interactions as a drug enters the binding site?

Answer 20

Ionic bonds

Question 21

How strong are van der Waals forces?

Answer 21

Very weak interactions (2-4 kJmol-1)

Question 22

How do van der Waals forces occur?

Answer 22

Occur between hydrophobic regions of the drug and the target

Due to transient areas of high and low electron densities leading to temporary dipoles

Question 23

How do van der Waals bond strength respond to distance?

Answer 23

Interactions drop off rapidly with distance

Drug must be close to the binding region for interactions to occur

Question 24

Are van der Waals forces important in drug binding?

Answer 24

Although weak bonds separately, the overall contribution of van der Waals interactions can be crucial to binding

Question 25

When can dipole-dipole reactions occur?

Answer 25

if the drug and the binding site have dipole moments

Question 26

How do dipole-dipole forces occur?

Answer 26

Dipoles align with each other as the drug enters the binding site

Dipole alignment orientates the molecule in the binding site

Question 27

Referring to dipole-dipole bonding, when is orientation beneficial?

Answer 27

if other binding groups are positioned correctly with respect to the corresponding binding regions

Question 28

Referring to dipole-dipole bonding, when is orientation detrimental?

Answer 28

if the binding groups are not positioned correctly with respect to corresponding binding regions

Question 29

How do dipole-dipole bonds change with distance in comparison to electrostatic and van der Waals interactions?

Answer 29

The strength of the interaction decreases with distance more quickly than with electrostatic interactions, but less quickly than with van der Waals interactions

Question 30

When do ion-dipole interactions occur?

Answer 30

Occur where the charge on one molecule interacts with the dipole moment of another

Question 31

Describe the strength of ion-dipole interactions compared to that of dipole-dipole interactions

Answer 31

Stronger than a dipole-dipole interaction

Strength of interaction falls off less rapidly with distance than for a dipole-dipole interaction

Question 32

When do induced dipole reactions occur?

Answer 32

Occur where the charge on one molecule induces a dipole on another
Occurs between a quaternary ammonium ion and an aromatic ring

Question 33

When and how do hydrophobic reaction occur?

Answer 33

Hydrophobic regions of a drug and its target are not solvated
Water molecules interact with each other and form an ordered layer next to hydrophobic regions - negative entropy
Interactions between the hydrophobic interactions of a drug and its target ‘free up’ the ordered water molecules
Results in an increase in entropy
Beneficial to binding energy

Question 34

What is QSAR

Answer 34

Quantitative Structure/Activity Relationships

Question 35

What is the most important physical property affecting potency, distribution and elimination

Answer 35

Lipophilicity

Question 36

What does lipophilicity affect?

Answer 36

aqueous solubility

		- permeability
		- receptor/enzyme binding
		- metabolism
		- plasma protein binding

Question 37

Describe ethers, chloroform and halothane in relation to their potency

Answer 37

ether < chloroform < halothane

Question 38

What are Hammett constants (σx) ?

Answer 38

These are measure of the electron donating or withdrawing power of a substituent; derived initially from substituted benzoic acids.

Question 39

Give the equation relating to Hammett constants

Answer 39

σx = pKa (substituted acid) – pKa (unsubstituted acid)

Question 40

Which of the following will partition into the phospholipid bilayer
An ionised compound or an unionised one?

Answer 40

Only the unionised one
According to this approximation, the drug needs to be in its uncharged (i.e. UNIONISED) form at the membrane surface to permeate the membrane by PASSIVE DIFFUSION

Question 41

The concentration of the compound passing through the membrane barrier depends upon what?

Answer 41

The percentage of the compound which is unionised

Question 42

The % of UNONISED compound is controlled by what?

Answer 42

its pKa and the pH of the solution

Question 43

Henderson-Hasselbach equation for a weak base

Answer 43

pH = pKa + log10[B]
______
[BH+]