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dan - Coggle Diagram
dan
discovery, dosing, delivery, sourcing
therapeutic window: range of drug dosage which provides effective treatment without toxic side effects
half life: time it takes for drug conc to fall by half in the body --> helps with dosing to reach therapeutic window
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primary metabolites: guides for design that are already involved in system (amino acids, nucleotides)
secondary metabolites: complicated and diverse and nonessential for normal growth but provide an evolutionary advantage
solid phase creation of synthetic compound: compound linked to resing and linker --> find complement to compound--> cleave linker --> isolate compliment
able to remove impurities, complete full rxn, small
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privileged scaffolds: commonly present structures on known drugs but can be used and substituents can be changed to have new effects
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peptidominetrics: peptides as drug source even though they have poor bioavailability orally and intravenously
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methylation
- disguise peptide bond
- retain stereochem
- can be steric shield
- can prevent important target interactions
invert stereocenter
- not recognizable by metabolic enzymes
- may not be recognized at target binding site
introduce unnatural residue
- unrecognizable to metabolic enzyme
- inc selectivity and aqueous solubility
extend side chain
- better oral bioavailability
- can bind two binding sites
targeting
target-based: find target and then design drug to modulate it. must validate if that modulation would work and then understand the selectivity of pathogen and target
easy + cheap + accurate measure of binding interactions but doesn't measure ability to get drug to target, side effects or false positives
cell-based: measure an observable phenotype in cell (size, protein expression)
know side effects and drug reaching and interacting with target is ensured but it is hard to known and validate the target and also $$$
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structure based lead design: known binding site and binding interactions and screening against a purified target
ligand based lead design: unknown target but ligand structure is known and modified to match activity. screening against cells
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drug basics
phases:
pharmaceutical, pharmacokinetic, pharmacodynamic
journey:
- GIT
- blood
- liver --> metabolicm
- blood again
- target
- excretion
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blood brain barrier: hinders polar drugs from entering brain because the tight-fitting cells require small, rigid and lipophillic drugs
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ADME: absorption, distribution, metabolism, excretion
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lipinksi's rule of five 
oral: patient-administered but has to survive a lot of shit
inhalation: less strong membrane to cross --> no first pass
injection: rapid! but side effect regulation = hard --> no first pass
transdermal: need to be soluble in fat and water -- no first pass
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optimizing drugs
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binding properties
vary or expand ring
- optimize binding interactions
- can help optimize interactions
- good for getting around patents
isoteres
- optimizes binding properties
- replace functional group with a group with the same valency
simplification:
- optimize binding interactions
- synthesis of analogues is easier
- more specificity for binding site --> less toxic
- must retain pharmacophore and remove unnecessary groups
- ex: cocaine
but! oversimplification can result in decreased activity
rigidification
- optimize binding interactions
- limit conformations
- increase selectivity
- molecule can be more difficult to synthesize
introducing rings, alkenes and steric blocks helps
drug extension
- optimize binding interaction
- can explore binding site for further possible interactions
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metabolic stability
N stabilization
- optimizes metabolic stability
- N giving e- to carbonyl makes it less prone to Nu attack
metabolic blockers
- optimize metabolic stability
- inc half-life
remove/replace/shift metabolic groups
- optimizes metabolic stability
- drugs must still be recognizable to target
introduce susceptible metabolic groups
- does NOT optimize metabolic stability
- used for drugs that linger too long
- often groups susceptible to phase 1 or 2 metabolism are added
steric shields
- optimizes metabolic stability
- protects susceptible functional groups
introduce chemically susceptible groups
- does NOT optimize drug life
- dec drug life
reducing drug toxicity
- remove/replace toxic functional groups
- vary substituents
- vary position and substituents