Drug Discovery Flashcards
How does the split and mix approach to combinatorial synthesis work?
Solid-phase synthesis, working with polymer beads. Add reagent to each well with multiple beads. Recombine and mix new reagent into each well. Split.
How is a target identified? What type of drugs are made from the pharmaceutical company’s point of view?
Drug development for first drug on market or best drug. First drug - disease with big enough market with no existing treatments. Best drug - new target for old disease, or new types of compound with better properties.
What is the pharmacophore?
Atoms and functional groups required for activity and their relative positions in space.
How are SAR methods used for drug optimisation?
Once pharmacophore identified, model drug activity, referring to parameters mathematically. Properties that may affect SAR are Hammett substituent constants, log P values, hydrophobicity constants and sterics.
How is the QSAR cycle used for drug optimisation?
Remove section of data set to validate model randomly. Use rest of set to produce working model and gradually refine model by feature elimination to find what parameters have an impact using trial and error or predictive algorithms. Validation done on removed piece of set until activity correctly predicted with final model.
What are the stages in drug development and what is done in each?
Target identification = something to treat, select target
Screening = screen active compounds from compound libraries
Hit = hits identified from screening
Lead = further processing of hits leads to lead
Lead Optimisation = lots of optimisation processes, via SAR, QSAR, clinical development
Candidate = final one put up for regulartory approval.
What are the key challenges in scaling up synthesis of a candidate drug?
Surface area to volume ratio poorer, resulting in poor heat transfer.
Safety of reactions impacted by potential for thermal runaway.
Mass transfer and heat transfer performances may both be impeded.
Toxic ramifications in even trace amounts, e.g. metal catalysts.
High costs of reagents.
Use of different purification techniques, ideally run clean reactions.
