Medicinal chemistry 3 - Sources of lead compounds continued

Question 1

What are endogenous compounds?

Answer 1

• They are compounds that occur naturally in the body

Question 2

Give 4 examples of endogenous compounds?

Answer 2

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

Question 3

What are some of the issues for using NTs?

Answer 3

• They would not survive stomach acid
• The body efficiently removes them
• They are hard to direct to one target in the body

Question 4

What are hormones and what are their issues, provide an example?

Answer 4

• They are peptides and proteins
• e.g insulin
• Issues are that they are susceptible to metabolic breakdown

Question 5

Give an example of a peptide in drug and state what it is used for and how is it administered?

Answer 5

• Zoladex - Goserelin
• Used to treat breast and prostate cancer
• Given by subcutabeous injection

Question 6

What do peptidomimetics do?

Answer 6

They mimic peptide bonds

Question 7

What do the Alkene, Ketone, Amine and N-methylation do (peptidomimetics)?

Answer 7

Alkene - provides rigidity
Ketone - Maintains C=O
Amine - Maintains N-H
N-methylation - Analogue without H-donor

Question 8

What is combinatorial chemistry?

Answer 8

• To match advances in genomics and proteomics

Question 9

What is computer aided design useful for?

Answer 9

• Useful if able to crystallise the enzyme or receptor

Question 10

What is X ray crystallography used for and what does it allow us to do?

Answer 10

• Poweful tool
• Helps in gaining detailed knowledge of the target binding site
• It allows us to duck a variety of structures into the bidning pocket

Question 11

What are the drawbaks for X ray crystallisation?

Answer 11

• Need crystal structure for accurate interpretation (this is very tricky)

Question 12

What does the dock program do?

Answer 12

Defines space in the building site using spheres

Question 13

What is a pharmacophore?

Answer 13

• It is the structure that has the important binding groups in the correct position

Question 14

What does De novo design involve?

Answer 14

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

Question 15

What are the advantages of using De novo design?

Answer 15

• Supplies novel pharmaceutical agents
• It is a time and cost efficient process
• It is a compliment to other virtual techniques

Question 16

What does ADMET stand for?

Answer 16

A-absorption 
D- distribution
M- metabolism 
E- elimination 
T- toxicology

Question 17

What are the three stages of optimization at a kinase active site?

Answer 17

1. Empty pocket
2. mM hit bound
3. nM lead compound

Question 18

What is an anti-target?

Answer 18

It is how selective your molecule is for a particular or similar binding site

Question 19

What acn you compare with anti-target?

Answer 19

• Electrostatic charge distribution
• Flexibility
• Hydrophobicity
• Strain energy

Question 20

What is serendipity (a.k.a mustard gas) used for?

Answer 20

• Useful in the treatment of leukemia

Question 21

Leukemia is a cancer which results in excess proliferation of white blood cells, so on this occasion killing cells is useful. TRUE OR FALSE?

Answer 21

TRUE

Question 22

What can NMR be performed on?

Answer 22

• Solids, liquids and oils

Question 23

If sample is too little for NMR, MS can be used instead and epitopes can be used. TRUE OR FALSE?

Answer 23

TRUE

Question 24

What are epitopes?

Answer 24

They are small molecules to bind to specific, yet different regions of the binding pocket

Question 25

What are the advantages of NMR detection?

Answer 25

- Screens 100's of small MW compounds - Can detect even weak binding - Identity binding to different regions of protein - Complements HTS - Enables progression if different/ weak binding identitified

Question 26

What is a major limitation to NMR screening?

Answer 26

- Need for arleast 200mg of protein / need pure protein