Lecture 2 Biochemistry, Combinatorial Chemistry, Automation
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Lecture 2 PHC320 Biochemistry, Combinatorial Chemistry, Automation
Cell-based assay: reverse disease based on general disease phenotype
Target-based: reverse disease based on molecular understanding
Mechanisms of action understood better
•E.g. division of antibiotics into those inhibiting RNA, DNA, or protein synthesis.
Resistance to antibiotics necessitated understanding of MOA. Serendipitous
discovery becoming ineffective
Scientists derivatize molecules with increased potency (Medicinal Chemistry), make
improvements
Old School Cell-Based Target-Based
Unknown mechanism Protein Target pre-determined
Lead molecule may be toxic Lead molecule highly specific less toxic
Context relevant (in vivo) In vitro; new FDA requirement for MOA
Disease state hard to reverse Target validation provides disease relevance
Hard to quantitate <nM efficacy can be achieved
New School Cell-based
•Too many “me too” drugs
•Vioxx specificity may not always be advantageous
•“polypharmacology”: no drug likely hits one target
•“systems biology”, “ex vivo”
•new targets, new pharma abandon antibiotics
•new quantitative targets, still difficult to identify MOA
High throughput screening (HTS)
•large number of compounds tested in automated fashion for activity as inhibitors or
activators of a particular biological target (cell surface receptor, metabolic enzyme)
Biochemistry (advantages/disadvantages)
•cell-based assays not readily quantifiable
•discovery of small molecule inhibitors in cell-based assays difficult to uncover
disease therapies
•low throughput, lots of compounds required
•works “in vivo”, but no known MOA, resistance developed
•recombinant technology allows large quantities of proteins to be made, and novel
biochemical assays to be developed
High throughput biochemistry + improved biological understanding
Target = cell membrane receptor
Binding assay
Rapid analysis of biochemical activities
Automation/Informatics
•Tubes 96 well plates 384 well plates 1536 well plates
•Yes/No screens, robots, HTS, rapid analysis, quantifiable detection, quantitative
readouts
Test with lower volumes, higher rates
Clinical trials: 10+ years, $1 billion +
Chemistry
•Natural products difficult to obtain large quantities, difficult to isolate single
compound
•Medicinal chemistry improvements, modification, greater efficacy
•Methods to synthesize many compounds in parallel, modify structure
Combinatorial chemistry: large number of compounds prepared at one time. Improvement
in synthetic chemical transformations
Combinatorial libraries – linear scaffold, globular scaffold
Reversible linkers, many combinations of different compounds
Notes from “Lessons from 60 years of pharmaceutical innovation”
•Despite investment in research and development, new drugs approved by the FDA
remains low
•New drug output from pharmaceutical companies has been constant despite
attempts to increase it
•New-drug outputs is not depressed, but may simply reflect the limitations of the
current R&D model
•New molecular entity (NME): medication containing an active ingredient that has
not been previously approved for marketing in any form in the US.
•Orphan Drug: a drug that is specifically developed for a disease that affects a
patient population of fewer than 200,000 people in the United States. The Orphan
Drug Act provides financial incentives to develop such drugs, including marketing
exclusivity for that indication for 7 years after approval
•Substantial number of small firms are developing orphan drugs and/or drugs that
are likely to gain priority review from the FDA owing to unmet medical needs.