Flashcards in Drug Design - Optimising Binding Interactions Deck (19):
How can lead compounds from the synthetic world aid drug design and development?
Combination of structure-based rational drug design and chemistry can be used for drug optimisation to produce synthetic drugs
Why would one want to optimise binding interactions with the target? Give a few reasons
To increase activity and solubility
Reduce dose levels
Hence reduce side effects
And reduce cost
To increase selectivity
Also to improve drug delivery by improving cellular penetration
Name some strategies of optimising binding interactions within a target
Vary alkyl/aryl substituents
Extension- chain extensions/contractions
Outline the general concept of varying akyl substituents to optimise binding interactions with a drug target
Give an example
Alkyl group in lead compound may interact with the hydrophobic region of the binding site.
Vary length and bulk of the alkyl group to optimise interaction
And/or to introduce selectivity
E.g. Bulky ligand may be more selective than a simpler one.
E.g. Selectivity of adrenergic agents for beta-receptors over alpha-receptors
State the structural difference and how this (impacts selectivity) between adrenaline, salbutamol and propranolol
At position R that varies
Adrenaline - 1 CH3 - least selective
Propranolol - 2 CH3 - intermediate selectivity
Salbutamol - 3 CH3 - most selective
Describe the rationale of chain extension in order to optimise binding
Give an example
Rationale: to explore target binding site for further binding regions to achieve additional binding interactions
E.g. ACE Inhibitors - add aryl group at hydrophobic pocket to improve binding
What is an aryl substituent?
How does varying aryl substituents optimise binding interactions?
Vary substitution/pattern or substituents themselves
By pattern - ortho, meta or para
Describe how chain extension/contraction can optimise binding interactions of drugs to their target sites
Chain extension/contraction is useful if a chain is present connecting the 2 binding groups
Vary length of chain to optimise interactions and increase potency
Why does screening of drug candidates occur? What are the tests like?
Required in order to find lead compounds for drug optimisation
Tests are in vivo or in vitro
Combination of tests are often used in research programmes
How does one establish testing procedures for screening of drug candidates? What should the tests be like in terms of attributes?
Choosing the correct bioassay is crucial for drug testing and to the success of drug discovery
Tests should be simple, quick, cost-efficient and relevant
When establishing testing procedures, what is the main challenge that one has to balance?
Must balance between:
-sufficient activity against the desired target
-minimise activity against other targets to reduce "off target" effect
What does the in vivo test for an anti-bacterial agent involve?
Infecting a test subject (animal) with a bacterial strain
Then giving the antibacterial agent to the animal to see if it combats infection
What are in vivo tests carried out on?
Living systems i.e. Animals and human volunteers
What is considered to be in vitro testing of an antibacterial agent?
Testing the antibacterial agents on microbiological cultures is considered to be in-vitro testing
What compounds are in-vitro tests carried out on?
In vitro tests are carried out on:
What is an enzyme assay used for?
To evaluate the level of enzyme inhibition and the mode of inhibition (competitive, non-competitive, reversible/irreversible)
To measure the concentration of ligand to suppress 50% of the enzyme i.e. The IC50
What is IC50? What does it show?
The concentration of ligand to suppress 50% of activity of the enzyme
IC50 shows strength of inhibition
Low IC50 = more powerful (potent) as smaller dose required the achieve the biological effect