Med Chem 3

Question 1

5) Natural ligand (e.g. for receptor)

Answer 1

5-HT, 5-hydroxytryptamine was the starting point for the development of 5-HT1 agonist, Sumatriptan

Question 2

Endogenous compounds as drugs

Answer 2

so compounds that are naturally occurring in the body e.g. hormones, neurotransmitters etc.

1) Neurotransmitters
2) Hormones
3) Peptides in drugs
4) Peptidomimetics

Question 3

Endogenous compounds as drugs 1) Neurotransmitters

Answer 3

• would not survive stomach acids
• body efficiently removes them
• hard to direct to one target in the body (therefore have side effects)

Medicinal chemists use receptor subtypes that are common to the specific tissues - in this way, the chemist is ahead of Nature!

Question 4

Endogenous compounds as drugs

2) Hormones

Answer 4

• most are peptides & proteins (e.g. insulin)

- susceptible to metabolic breakdown

Question 5

Endogenous compounds as drugs

3) Peptides in drugs

Answer 5

Goserelin (Zoladex)

$700 million / year - used for breast and prostate cancer (given by subcutaneous injection)

Question 6

Endogenous compounds as drugs

4) Peptidomimetics

Answer 6

Modifications to the peptide bond:

• Alkene - still provides rigidity
• Ketone - maintains C=O
• Amine - maintains N-H
• N-methylation - analogue without H-donor

If activity is retained we have a bioisostere

Question 7

6) Combinatorial chemistry (combi-chem)

Answer 7

• To match advances in genomics and proteomics
• Automated solid-phase procedure
• Many structures in less time
• Small scale reactions
• Artificial production to try and compete with nature

Question 8

The current approach to lead compounds….

Answer 8

Combinatorial synthesis answers the explosion in the number of drug targets
‘finding a lead was becoming the limiting factor in the pharmaceutical industry’
‘produce 1000’s or millions of novel structures in the same time as a dozen by conventional means’

Question 9

7) Computer aided design

Answer 9

§ Useful if we are able to crystallize the enzyme or receptor
§ X-ray crystallography - a very powerful tool
§ Gain a detailed knowledge of the target binding site
§ Model software allows us to dock a variety of structures into the binding pocket

Drawback! Need the crystal structure for accurate interpretation. This is very tricky!!

Question 10

Docking ….

Answer 10

The DOCK program - defines space in the binding site using spheres

• The spheres, which can overlap with one another, must touch the molecular surface twice (& twice only)

Question 11

Pharmacophore ID….

Answer 11

Pharmacophore = structure that has the important binding groups in the correct position

Question 12

De novo design….

Answer 12

• involves the design of novel structures based on the structure of the intended binding site

§ This technique was conceived approx. 20 years ago
§ Supplies novel pharmaceutical agents
§ Is a cost and time efficient process
§ A complement to other virtual techniques (e.g. database searching)

Question 13

Predictive ADMET studies….

Answer 13

ADMET = Absorption, distribution, metabolism, elimination and toxicology
This predictive computational technique is described as, the new ‘hip’ area in drug design

Question 14

Three stages of optimization at a kinase active site….

Answer 14

• Empty pocket
• mM hit bound
• nM lead compound

Optimization is based on information relating to the 3D shape and chemical nature of the active pocket

Question 15

An anti-target

Answer 15

is a protein with similar structures that chemists
should design away from in order to avoid unintentional
interactions & potential side effects.
Can compare, electrostatic charge distribution, flexibility, hydrophobicity, strain energy etc.

Question 16

8) Serendipity

Answer 16

Example: Mustard gas
US war ship exploded in an Italian harbor.
Survivors lost natural defense against microbes (white blood cells were destroyed).
Useful in the treatment of Leukemia

Leukemia - a cancer which results in excess proliferation of white blood cells. So on this occasion, killing cells is useful.

Question 17

9) NMR strategy

Answer 17

• NMR can be performed on solids, liquids and oils.
• If too little is present we can do MS.
• We can use epitopes

Question 18

Epitopes

Answer 18

Small molecules to bind to specific, yet different regions of the binding pocket.
This allows us to build up a bigger picture

Question 19

9) NMR strategy
Screening by NMR
- Advantages of NMR detection:
and major limitation

Answer 19

1) Screen 100’s of small MW compounds / day on one machine
2) Can detect even weak binding
3) Identify binding to different regions of protein (new bonding sites)
4) Complements HTS (can reinforce findings from HTS)
5) Enables progression (new leads) if different / weak binding ID’d

• Major limitation - Need for at least 200mg of protein