L26 - Introduction To Drug Discovery And Design

Question 1

What does drug design cover?

Answer 1

The identification and optimisation of the API

Question 2

Where does the API come from?

Answer 2

• natural products
  = earliest source of drugs
• semi-synthetic
  = derivaties of natural products, receptor selectivity
• synthetic
  = small molecule, large biological drugs

Question 3

What is the Ebers Papyrus?

Answer 3

Oldest compendiums of treatments for disease (1550BC)
- mentions mental disorders and remedies (depression and dementia)

Question 4

What are sources of natural products?

Answer 4

From cells, tissues and secretions
- microorganisms (penicilin)
- plants (morphine)
- animals (conotoxins)

Question 5

Where is morphine derived from?

Answer 5

Seedpods of the poppy

Question 6

What is the history of morphine?

Answer 6

1800’s: opium a painkiller
1783-1841: isolate the active ingredient in opium
Mid 1820’s: producing standardised doses of the drug

Initially marketed as: non addictive cure for addiction to both alcohol and opium

Question 7

What are examples of other natural products?

Answer 7

• doxorubicin
• erthromycin A
• steptomycin
• cyclosporin A
• taxol

(Antibiotics)

Question 8

What are semi-synthetic drugs?

Answer 8

Synthesising a particular chemical using naturally occuring chemicals as a starting material

Question 9

What are the advantages of semi-synthesis?

Answer 9

• moleculres are too complex and too difficult to synthesis chemically
• limited availability from natural sources
• altered receptor selectivity, improves specificity = addtional/alternative uses

Question 10

What is an example of a semi-synthetic drug?

Answer 10

Taxol

Question 11

How does taxol work?

Answer 11

Cell division by binding to the protein tubulin, prevents mitosis
- potential source of anticancer drugs from yew bark

Question 12

What can result from modification of morphine?

Answer 12

Opioid analogues with varying potency and receptor specificity

Question 13

What can chemical modifications to morphine change?

Answer 13

Which receptor type the compound binds to and the effect it causes

Question 14

What are synthethic drugs?

Answer 14

Synthesis of drugs using chemical methods, starting from readily available materials

Question 15

What are advantages to synthetic drugs?

Answer 15

• reliability of production
• cost effective
• quality control

Question 16

What are disadvantages of synthetic drugs?

Answer 16

• limited chemical space
• limited number of steps

Question 17

What is rational drugs design?

Answer 17

Rationally discover the identity of the API using a series of techniques and methods

Question 18

What targets can we focus on when designing a drug?

Answer 18

• enzymes
• receptors
• ion channels

Question 19

What makes a target ‘druggable’?

Answer 19

• disease-modifying
• less important under physiological condition or in other diseases
• expression is not uniformly distributed throughout the body

Question 20

What are properties of an ideal drug target?

Answer 20

• 3D structure for the target protein/close homolog should be available for druggability assessment
• favourable assayability
• biomarker exists to monitor therapeutc efficacy
• favourable prediction of potential side effects
• target has a favourable IP situationL

Question 21

What are properties of drug-like molecules?

Answer 21

• low MW
• not too ipophilic
• not too hydrophilic
• presence of functional groups

Question 22

What are properties of druggable targets?

Answer 22

• protein
• leads to biological response
• does not cause toxicity

Question 23

What chemical properties should the drug have?

Answer 23

Lipinski’s Ro5
- MW < 500
- logP < 5
- < 5 H bond donors
- < 10 H bond acceptors

Question 24

What does a drug molecule possess?

Answer 24

Structural framework that holds the functinal groups in defined position

Question 25

What does the structural framework enable?

Answer 25

Molecule to bind specifically to a targeted biological macromolecule (receptor)

Question 26

What us biosiosteres?

Answer 26

Structually distinct molecular fragments

Question 27

What do bioisosteres need to be compatible with? Examples?

Answer 27

Variety of conditions in vivo
- solubility, absorption, stability, toxicit

Question 28

What are suitable chemical properties of drug like molecules?

Answer 28

• chemical stability
• solubility
• pKa

Question 29

What are suitable biological properties for drug molecules?

Answer 29

• biodistribution
• metabolism
• half-life
• solubility
• potency
• specificity
• toxicity

(Route of administration, dosage (amount/frequency), formulations)