early drug stage strategies
- fragment based combinatorial chemistry
- phenotypic screening
- virtual screening
- rational drug design
combinatorial chemistry use
develop a large bank of drug molecules in short period to treat large number of diseases.
step 1 = synthesis of building blocks bearing connecting x and y
step 2 = generation of combinatorial libraries by independent synthesis and purification
step 3 = lead identification by high-throughput screening, testing each compound for activity.
what is a phenotype
biochemical/physiological characteristics of an individual (extended to a disease state)
what is phenotypic screening?
- testing of small molecules that alter phenotype
tests a lot of drug molecules against different diseases. (e.g. taxol from tree bark for ovarian cancer)
(Screening means testing extracts against cell lines derived from a diverse array of human tumors (breast, stomach, lung, etc))
what is virtual screening?
computer based docking of diverse families of molecules
with homology models of the biological target.
virtual screening can be used instead of phenotypic screening because?
- it is less expensive
- no wet chemistry has to be done
- however, structure of biological target is not available
what is rational drug design for?
- druggability and target validation
- validate target involved in biomedical cascade of disease
- validate target responsive to small molecule treatment.
what is pharmacophore optimisation in rational drug design?
understanding the structure of the biological target leads to optimisation of the pharmacaphore.
what does QSAR stand for?
Quantitative structure activity relationship
what does the rational drug design process involve?
- identification of the natural ligand of the biological target
- mapping of molecular interactions between the ligand and target
- substitution of structural features of the natural ligand to create an agonist/antagonist.
