52 Questions
What is the purpose of high throughput screening (HTS) in drug development?
To test a vast number of compounds for biological activity
Describe the process of identifying the active compound in an equilibrium reaction.
Freezing the equilibrium reactions and performing an irreversible reaction to convert all equilibrium products to stable compounds
How are HTS assays mainly conducted?
Mostly optical assays (fluorescence, luminescence, absorbance)
What is the benefit of using multi-well plates with a higher number of wells in HTS assays?
Significant cost savings and less sample per assay
Explain the role of carbonic anhydrase in the DCS reaction mentioned in the text.
Acting as the target for the reaction
What is the significance of using irreversible reactions in shifting the equilibrium towards the active compound?
Generates more of the active compound (Amplification!)
What is the purpose of using photolithography in combinatorial chemistry?
To synthesize and detect specific products on a plate with high resolution.
Explain the concept of Safety Catch and acid-labile linker in solid phase extraction.
Safety Catch ensures the target molecule is safe on the linker until a specific step is performed, while acid-labile linker releases the target molecule with an acid treatment.
How does Dynamic Combinatorial Chemistry (DCS) differ from typical mix and split synthesis?
In DCS, all compounds are synthesized simultaneously in one flask and screened as they are formed, whereas mix and split synthesis involves sequential steps.
What role does the photolabile protecting group play in peptide synthesis using photolithography?
The group is used for deprotection of specific sites on the solid support, allowing coupling with protected amino acids.
How are peptide microsequencing and bead-based synthesis related in combinatorial chemistry?
Peptide microsequencing helps determine the code attached to the Lys residue on beads, allowing identification of synthesized peptides.
Explain the concept of peptide chains with different sequences in parallel synthesis using masks.
Different masks expose specific areas on the plate for deprotection, leading to the synthesis of peptide chains with varied sequences.
What are the two ways of generating an array of compounds for finding hits and leads in drug discovery?
Combinatorial synthesis (CS) and Parallel synthesis (PS)
What is the advantage of Parallel Synthesis (PS) over Combinatorial Synthesis (CS) in terms of structure identification?
Easier to identify the synthesized structures in PS.
Why is Combinatorial Synthesis (CS) valuable for finding leads in drug discovery?
Generation of many more structures compared to PS.
What was the first example of solid-phase synthesis mentioned in the text?
Merrifield resin peptide synthesis
Why is the Merrifield resin rarely used these days in peptide synthesis?
Polystyrene is too hydrophobic, leading to peptide chain folding in on itself.
What are the names of more modern resins used in peptide synthesis?
Wang and Rink resins
What type of molecules were early solid-phase synthesis efforts concentrated on, despite their poor pharmacokinetic properties?
Peptides
What is the role of benzodiazepines like Valium as positive allosteric effectors?
GABAA receptors modulation
How are spider-like scaffolds used in the design of compound libraries?
To achieve structural diversity by having a central body and arms bearing different functional groups.
What is the importance of having evenly spaced arms in spider-like scaffolds for compound library design?
Higher success rates for finding leads due to better exploration of 3D space around the molecule.
What are the other multi-component reaction reaction type that have been used to generate large compound libraries?
Ugi, Biginelli, Passerini reaction
How does fluorous solid-phase extraction (F-SPE) differ from basic column extraction?
F-SPE uses highly fluorinated silica to remove fluorinated compounds, while basic column extraction removes acidic impurities.
What is the purpose of using scavenger resins in Parallel Synthesis (PS) work up?
Scavenger resins are used to eliminate excess reagent and yield pure product.
Describe the Catch-and-Release strategy mentioned in the text.
Catch-and-Release involves attaching a reagent to a resin, which can be easily removed by filtration after the reaction is completed.
In amide synthesis using carbodiimide urea, what are the three main components involved?
Carboxylic acid, coupling reagent (resin-bound), and existing questions.
How can excess amine be efficiently removed after forming the urea derivative in a reaction?
Excess amine is consumed by adding fluorinated isocyanate after the reaction, and then the fluorinated urea derivative is removed by F-SPE.
What are the advantages of using microfluidics in parallel synthesis?
Shorter reaction times, fewer by-products, higher yield, good control of temperature, potential for a vast number of chemical reactions on one chip
Explain the mix-and-split method in combinatorial synthesis.
It is a method that allows for the generation of multiple compounds by mixing and then splitting them, saving time compared to individual syntheses.
What is the purpose of combinatorial synthesis (CS) in drug discovery?
To generate large amounts of compounds quickly for testing biological activity as mixtures.
How does microwave-assisted organic synthesis (MAOS) differ from conventional synthesis?
MAOS accelerates synthesis using microwaves, resulting in higher efficiency and often greener processes.
What is the role of the mix-and-split method in generating compounds in combinatorial synthesis?
It enables the synthesis of compounds from multiple building blocks simultaneously, reducing the time and effort required.
How does the mix-and-split method benefit the synthesis of a dipeptide from 5 amino acids?
It allows for the generation of the dipeptide in less time by combining and splitting the building blocks efficiently.
What is the purpose of using bifunctional linkers like SCAL in compound synthesis?
To help with structural identification by tagging/coding compounds
Explain the concept of compound tagging in the context of a 3-step synthesis using SCAL.
Tags are used to code each synthetic step, allowing for the identification of the specific sequence of the final compound.
How can the target molecule on the Trp residue be released after the last synthetic step?
In two steps: one involving the cleavage of the tag, followed by the release of the target molecule.
What is the significance of performing syntheses with beads that harbor bifunctional linkers in compound identification?
It allows for the structural identification of compounds in a mixture by utilizing tagging/coding techniques.
In a 3-step synthesis using SCAL, what does each tag represent?
Each tag corresponds to a specific synthetic step in the synthesis process.
How does the use of bifunctional linkers like SCAL contribute to compound synthesis and identification?
It facilitates both the synthesis of target molecules and the coding of compounds, aiding in structural identification.
What is the purpose of peptide microsequencing in combinatorial chemistry?
To determine the code attached to the bead
How does photolithography contribute to peptide synthesis?
By exposing specific parts of the surface with light for deprotection
What are the key aspects of Dynamic Combinatorial Chemistry (DCS)?
Target presence, reversible reactions, and selective binding of active compounds
Explain the concept of Safety Catch in solid-phase extraction.
Safety catch ensures the target molecule is safe on the linker until a specific step is performed
How does the process of photolithography allow for the creation of peptide chains with different sequences?
By using different masks in each synthesis cycle
What is the main advantage of Parallel Synthesis (PS) over Combinatorial Synthesis (CS) in terms of structure identification?
PS allows for the generation of known structures at specific locations
What is the purpose of High Throughput Screening (HTS) in drug development?
To test a vast number of compounds for biological activity.
How are HTS assays mainly conducted?
HTS assays are mostly optical assays, such as fluorescence, luminescence, and absorbance.
Why was the sulfonamide compound significantly amplified in the DCS reaction?
The irreversible reaction used reduced all equilibrium products to stable compounds, shifting the equilibrium towards the active compound.
Describe the process of identifying the active compound in an equilibrium reaction.
The process involves freezing the equilibrium reactions and performing an irreversible reaction to convert all products to stable compounds.
What is the significance of using irreversible reactions in shifting the equilibrium towards the active compound?
Irreversible reactions convert all equilibrium products to stable compounds, amplifying the active compound.
What are the main features of High Throughput Screening (HTS) systems like the UltraHTS system at Bristol-Myers Squibb?
HTS systems are heavily automated, using large compound storage facilities and computer-controlled robots for sample handling.
Learn about the two ways of generating compound libraries - Combinatorial Synthesis (CS) and Parallel Synthesis (PS). Understand the advantages of each method and their implications in finding hits and leads in drug discovery.
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