New Directions in Drug Discovery

1. "Mining" Genome and 3-D Structure Information


* deduce function based on sequence information (related genes, families)


* use genes and gene products as drugs (limited)


* get all subunits of all classes of a protein; check for differences, similarities that may tell roles in the cell


* find all motifs, folds, & domains from crystal and NMR structures that perform certain functions - use to build "new" structures with useful designer functions


2. Mapping


* "pre-genomics" used positional cloning or pedigree analysis, chromosome markers


* with genomics and SNP (Single Nucleotide Polymorphisms), pedigree analysis of selected families with disease (fast!)


3. Expression Profiling


* cDNA or oligonucleotide arrays in various states of disease, tissue or tumor - use as probes or to find leads into the problem


4. Comparative Genomics


* compare pathways in various organisms


* find basic cellular processes and signal transduction pathways established early in and conserved during evolution


* use genetically modifiable or pliant model (e.g. C. elegans worm, Drosophila fly) organisms to discover pathways and genes involved then go to human genes / pathways (can quickly grow large numbers and easily mutate/alter the model organisms)


5. Screening Technologies


* HTS (High Throughput Screening) - integration of technologies to rapidly assay thousands of compounds for bioactivity. Find a lead or active molecule that can be improved using very small amounts of reagents.
a. high density microplates (96 wells; 1,536 wells)

b. high-density microchips or arrays

c. microfluidic arrays and chips

d. robotic handling and automation


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