Theme 3 Lecture 12 Flashcards
Define combinatorial libraries and give an example. 2d
Combinatorial libraries are large (>100 compounds) collections of structurally related compounds. An example is a 2-dimensional matrix of compounds.
Explain the concept of a 2-dimensional matrix in combinatorial libraries.
A 2-D matrix involves creating compounds from a set of reagents (building blocks) arranged in a matrix format, based on a common scaffold.
What are the considerations regarding the number of compounds in a combinatorial library? lipinski’s rule of 5(cherry picking)
The size of libraries can increase dramatically. It’s crucial to be selective in making compounds, considering factors like Lipinski’s Rule of Five.
How does a 3-dimensional matrix differ from a 2-dimensional one in combinatorial libraries? (reagents)
Involves an additional dimension of reagents which in turn increases the library size.
What are the major practical issues in the synthesis of large compound libraries?
Purification of the pure products.
what is parallel synthesis(s,p,h)
Involves synthesizing, purifying and handling samples
Define split pool synthesis
Involves peptide synthesis and systemic connection of different building blocks to get different compounds.
Resin-based synthesis requirements(5)
Resin based surface or stable bonds, protecting groups, cleavage means or and anchor/linker.
Merrifield resin for peptide synthesis (ester bond)
Used to link amino acids via an ester bond to a resin bead for synthesis and deprotection of peptides
Split pool synthesis process
Involves coupling building blocks to resin, pooling and splitting them and assembles compounds of the beads of resin
Contrast solid phase parallel chemistry with split-pool synthesis.
Unlike split pool synthesis it does not require deconvolution as each compound is prepared and purified.
What is deconvolution (solving a puzzle)
Deconvolution in drug discovery is like solving a puzzle to find out which specific chemicals in a large mix are effective for a particular purpose. Imagine mixing many different ingredients together and then figuring out which specific ones are doing the job you want. That’s what deconvolution does - it helps identify the effective ingredients from the mix.
Explain the major differences between split-pool combinatorial synthesis and parallel synthesis. COOKIES
Split pool synthesis is on the beads
Lower steps 3x3 trimers
Deconvolution needed
More efficient in terms of steps
Parallel synthesis needs 27 reactions as you add one group at each time but produces larger quantities.
Cookies analogy
What are DNA-encoded Libraries (DEL) and how are they used? tagged and weak structures
Uses DNA labelling for library design and deconvolution, building blocks are tagged with DNA and then assayed=weak structures of binders are the elucidated.
What is the goal of diversity-orientated synthesis in drug discovery?
DOS aims to generate diverse molecular scaffolds which is used for the discovery of candidates with unique biological activities.
Requires reactions that are high yielding and stereospecific
