L26 - Introduction To Drug Discovery And Design Flashcards
What does drug design cover?
The identification and optimisation of the API
Where does the API come from? (3)
- natural products
= earliest source of drugs - semi-synthetic
= derivaties of natural products, receptor selectivity - synthetic
= small molecule, large biological drugs
What is the Ebers Papyrus?
Oldest compendiums of treatments for disease (1550BC)
- mentions mental disorders and remedies (depression and dementia)
What are sources of natural products? (3)
From cells, tissues and secretions
- microorganisms (penicilin)
- plants (morphine)
- animals (conotoxins)
Where is morphine derived from?
Seedpods of the poppy
What is the history of morphine?
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
What are examples of other natural products? (5)
- doxorubicin
- erthromycin A
- steptomycin
- cyclosporin A
- taxol
(Antibiotics)
What are semi-synthetic drugs?
Synthesising a particular chemical using naturally occuring chemicals as a starting material
What are the advantages of semi-synthesis? (3)
- moleculres are too complex and too difficult to synthesis chemically
- limited availability from natural sources
- altered receptor selectivity, improves specificity = addtional/alternative uses
What is an example of a semi-synthetic drug?
Taxol
How does taxol work?
Cell division by binding to the protein tubulin, prevents mitosis
- potential source of anticancer drugs from yew bark
What can result from modification of morphine?
Opioid analogues with varying potency and receptor specificity
What can chemical modifications to morphine change?
Which receptor type the compound binds to and the effect it causes
What are synthethic drugs?
Synthesis of drugs using chemical methods, starting from readily available materials
What are advantages to synthetic drugs? (3)
- reliability of production
- cost effective
- quality control
What are disadvantages of synthetic drugs? (2)
- limited chemical space
- limited number of steps
What is rational drugs design?
Rationally discover the identity of the API using a series of techniques and methods
What targets can we focus on when designing a drug? (3)
- enzymes
- receptors
- ion channels
What makes a target ‘druggable’? (3)
- disease-modifying
- less important under physiological condition or in other diseases
- expression is not uniformly distributed throughout the body
What are properties of an ideal drug target? (5)
- 3D structure for target protein/close homolog should be available for druggability assessment
- favourable assay ability
- biomarker exists to monitor therapeutic efficacy
- favourable prediction of potential side effects
- target has a favourable IP situational
What are properties of drug-like molecules? (4)
- low MW
- not too ipophilic
- not too hydrophilic
- presence of functional groups
What are properties of druggable targets? (3)
- protein
- leads to biological response
- does not cause toxicity
What chemical properties should the drug have?
Lipinski’s Ro5
- MW < 500
- logP < 5
- < 5 H bond donors
- < 10 H bond acceptors
What does a drug molecule possess?
Structural framework that holds the functinal groups in defined position
What does the structural framework enable?
Molecule to bind specifically to a targeted biological macromolecule (receptor)
What is bioisosteres?
Structually distinct molecular fragments
What do bioisosteres need to be compatible with? Examples?
Variety of conditions in vivo
- solubility, absorption, stability, toxicit
What are suitable chemical properties of drug like molecules? (3)
- chemical stability
- solubility
- pKa
What are suitable biological properties for drug molecules? (7)
- biodistribution
- metabolism
- half-life
- solubility
- potency
- specificity
- toxicity
(Route of administration, dosage (amount/frequency), formulations)
