Drug Design - Optimising Binding Interactions Flashcards
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 Ring expansions/contractions Isoteres Simplification Rigidification
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?
R-benzene ring
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?
Main challenge
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
